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INDIAN JOURNAL OF ANAESTHESIA, OCTOBER 2004340 PG ISSUE : PAED ANAESTHIndian J. Anaesth. 2004; 48 (5) : 340-346

1. D.A.,M.D., Prof.

2. M.D.

3. D.A.

Department of Anaesthesiology

Christian Medical College, Vellore,

Tamil Nadu, India- 632004

Correspond to :

Dr. Rebecca Jacob

E-mail : [email protected]

PHARMACOKINETICS AND PHARMACODYNAMICS OF

ANAESTHETIC DRUGS IN PAEDIATRICSDr. Rebecca Jacob1 Dr. Krishnan B. S.2 Dr. Venkatesan T.3

Introduction

Pharmacokinetics and pharmacodynamics of

drugs and inhalational agents used in anaesthesia have

been studied extensively. However, it is only recently

that some of the flaws in the studies and the use of drugs

have been noted.1For example, we know that all inhalational

agents potentiate the effects of nondepolarizing muscle

relaxants, but it must be remembered that this effect is

both age and time dependent. Firstly, infants and youngchildren more rapidly establish maximum potentiation

than older children do and secondly this potentiation

reaches maximum levels only within 1-2 hours. Therefore,

pediatric studies related to potency, onset time or

maintenance requirement of muscle relaxant are often

difficult to compare as the duration of inhalational

anaesthesia may have varied considerably and is often

not even described. Another problem in analysis which

may arise is that monitoring of neuromuscular response

by accelerography produces results that may vary

from those of electro and mechanomyography in

comparative studies.1 The extrapolation of data fromadult studies without considering the drug effects on children

is another consideration. For example, the initial use of

prolonged infusions of aminoacid local anaesthetics in

the epidural space led to a number of cases of seizures

and cardiac arrest.2 Subsequent pharmacokinetic studies

have now helped formulate maximum safe infusion rates

for infants and children.

Pharmacokinetics of drugs in children3

The dual processes of pharmacokinetics and

pharmacodynamics of drugs administered to patients in

general is illustrated in the figure 1.

Absorption of drugs

Different modes are used to administer drugs to

children. The most common of these involve extravascular

routes preoperatively and postoperatively ,and intravenouslyin the operation theatre or ICU.

Oral : The efficacy of orally administered drugs

depends on the rate and extent of absorption from the

gastrointestinal tract (mainly the small intestine),

physicochemical nature of the drug, nature of gastrointestinal

juices, rate of gastrointestinal emptying and gut blood

flow.4,5 Several of these factors are affected in the neonate.

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 seenin 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

Fig. - 1

340

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REBECCA, KRISHNAN, VENKATESAN: PHARMACOKINETICS & PHARMACODYNAMICS OF ANAESTHETIC DRUGS 341

enzymatic changes in the neonate such as low activity

levels of cytochrome P-450 1A1 (CYP1A1) can alter the

bioavailability of drugs.3 Disadvantages of the oral route

include emesis, destruction of the drug by digestiveenzymes 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 or 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.4

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 densityof skeletal muscle capillaries in infants than older

children.5 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. However some drug may be lost

because it is adsorbed to the glass or plastic infusion system.

Its effects may be delayed if the infusion rate is slow.

This can lead to an incorrect conclusion about the patients

need for more or less drug.

Premedicant drugs such as morphine, pentobarbitalor atropine do not alter the volume of gastric juice but

glycopyrrolate does reduce the volume of gastric juice by

a third and increases the pH of 68% gastric samples to

above 2.5.5

Transdermal :This method provides sustained

therapeutic plasma drug concentrations and presently used

drugs in this method include fentanyl, clonidine, nitroglycerine

and EMLA.4 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.3 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 are given rectally to avoid some of

the problems of orally administered drugs. This route should

be avoided in immunosuppressed patients or those undergoing

chemotherapy.5 Drugs administered in the anal canal below

the ano-rectal or dentate line bypass the liver after

absorption, while drugs inserted 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. Premedicant drugs used per rectum includethiopentone, 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.

Developmental changes in the architecture of the lung and

its ventilatory capacity (eg. minute ventilation, vital capacity

and respiratory rate) can alter patterns of drug deposition

and hence systemic absorption after intrapulmonary

administration of drug.3

Irrespective of the route of administration of drug

(intravenous or inhalational), the expected anaesthetic

effect occurs only when the concentration of the drug at the

receptor site reaches the target concentration to produce

anaesthesia.

Uptake and Distribution (of drugs other than

inhalational agents)4, 5

Removal of a drug from the site of administration

and distribution to the effector site depends on cardiac

output, tissue perfusion and blood tissue partition co-efficient

of the drug. Age dependant changes influence the apparentvolume of distribution (Vd) of drugs. 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. Serum albumin

concentrations reach adult levels by 5 months of age.However, albumin only accounts for a small fraction of

drug binding. Another protein of significance which binds

drugs is a1acid - 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.

A reduction in the quantity of total plasma proteins

(including albumin) in the neonate increases the free fraction

of drug. This decreased binding of drugs to proteins, coupled

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INDIAN JOURNAL OF ANAESTHESIA, OCTOBER 2004342 PG ISSUE : PAED ANAESTH

with an incompletely developed blood brain barrier can

lead to accumulation of drugs like barbiturates and morphine

in the CNS of neonates.

Metabolism

Development of phase I and phase II enzymes :

Phase I reactions (oxidation, reduction and hydrolysis) are

cytochrome p-450 dependent. The activity of many

cytochrome P-450 isoforms including CYP3A4, CYP2C,

and CYP1A2 is markedly decreased in the first 2 months

of life.3 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. It is

seen that some phase II pathways (eg. sulfonation) are matureat birth while others (eg. glucuronidation) are not. 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. Levels

of UGT2B7 (responsible for glucuronidation of morphine)

are markedly diminished in the first 2 months of life.

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.

Excretion5

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. Renal drug clearance is also

affected by the renal extraction ratio and by glomerular

pore size. 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 neonates

reduced renal function can delay the drug elimination and

clinicians must individualize therapy in an age appropriate

fashion.

Individual drugs

Intravenous induction agents

Thiopentone Thiopentone requirements for induction

of anaesthesia reveal an inverse relation with age. A

significantly larger volume of distribution in the infant,

makes the ED-50 of thiopentone in infants significantly

greater (7 mgkg-1) than that in adults (4 mgkg-1).6 This

larger dose increases the store of drug in the body and

prolongs the drugs half-life. In neonates due to their low

body fat and muscle content, less thiopentone is apportioned

to these tissues; so concentration in the CNS may remain

high and delay awakening.

Benzodiazepines The premature and the matureinfant at term eliminate diazepam at a slower rate than

adults do. Differences in metabolism as described earlier

alter the way in which neonates and infants reduce the

plasma concentration of drugs. Neonates hydroxylate and

N-demethylate diazepam less well than adults or children

do which prolongs the elimination half-life of diazepam

(7538 hours in preterm infants as compared to 183

hours in children) and thus prolongs its effect.5

Ketamine In infants less than 3 months of age, the

Vd is similar to that in older infants but the elimination

Fig. 2 :Physiological factors that affect pharmacokinetics of drugs during their

absorption, distribution, metabolism and excretion

ABSORPTION1. Age dependent changes in structure and function of GIT, affect oral

absorption.

2. First pass hepatic metabolism is a problem that is avoided in oral

transmucosal drug administration.3. Skin thickness is similar in infants and adults, but extent of perfusion and

hydration diminishes from infancy to adulthood.

4. Rectal absorption of drugs is erratic and first pass hepatic metabolism

occurs in drugs administered above the ano-rectal line.

DISTRIBUTION

1. Age dependent changes in body composition, influence the apparentvolume of distribution of drugs.

2. In the first 6 months of life infants have an expanded total body water

and extracellular water, expressed as a percentage of total body weight ,

as compared with older infants and adults.

3. Reduced levels of fetal albumin and1 acid - glycoprotein contribute tothe increased free fraction of drug.

METABOLISM

1. The activity of many cytochrome P-450 (CYP) isoforms and a single

glucuronosyltransferase isoform is markedly decreased during the first 2months of life.2. The acquisition of adult activity over time is enzyme and isoform-

specific.

3. Compensatory pathways can help in drug metabolism.

4. Both phase I and phase II metabolic reactions mature by 1 year of age.

EXCRETION

The processes of glomerular filtration and active tubular secretion

approximate adult activity by 6-12 months of age.

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half-life is prolonged. Hence, clearance is reduced in the

younger infants. Reduced metabolism and renal excretion

in the young infant are the likely causes. The

pharmacokinetic details of ketamine are outlined in thetable 1.7

Table - 1 : Pharmacokinetics of ketamine : effect of age

Age T1/2

(min) VdSS (Lkg-1) C l (mlmin-1kg-1)

< 3 mo 184.7 3.46 12.9

4- 12 mo 65.1 3.03 35.0

4 y 31.6 1.18 25.1

Adult 107.3 0.75 20.0

T : Elimination half life; VdSS : Volume of distribution at steady state; CL : Clearance.

Propofol -Propofol has been used in the induction

and maintenance of general anaesthesia in children. In a

study done by Murat et al in 12 children aged between 1

and 3 years given a single dose of propofol 4 mgkg-1 an

average Vd of 9.53.7 Lkg-1 with an average total body

clearance of 5313 mlmin-1kg-1 was reported. Younger

children demonstrated a larger Vd with a similar rate of

clearance.8

Narcotics

Morphine Studies have demonstrated that morphine

depresses the respiratory centre of newborns more thandoes pethidine.9 When the brain uptake index (BUI) for

morphine was determined in developing rats, it was higher

in the younger than the older rats. Pharmacokinetic studies

of morphine also show that infants less than 1 week of age

demonstrate longer elimination half life compared to older

infants.10

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.5

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.11

Neuromuscular blocking drugs (NMBD)

Clinically most neuromuscular blocking drugs are

studied under anaesthesia as the children are first

anaesthetized and then the drugs given. Infants have a much

greater potentiation and reduction in dose requirements than

older children (sevoflurane decreases the dose requirement

of non depolarizing muscle relaxants by 70% if administered

for 90 min in school age children and 40 min in infants by

prolonging their duration of action.1

Depolarizing muscle relaxants On a weight basis

more succinylcholine is needed in infants than in older

children or adults.12 Succinylcholine is rapidly distributed

throughout the ECF because of its relatively small molecular

size. The blood volume and ECF volume in infants are

significantly greater than that of a child or adult on a

weight basis. 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.13

Non depolarizing muscle relaxants (NDMR) Thereis substantial evidence to suggest that the neuromuscular

junction in neonates is three times more sensitive to NDMRs

than that of adults. However this sensitivity is balanced by

an almost identical increase in the volume of distribution

(because of large ECF) so the required dose is unaffected.

However, because of a prolonged elimination time, doses

of additional relaxants should be reduced and given less

frequently.13 Children of all ages are more resistant than

adults to pancuronium.

Anticholinesterases Neuromuscular blockade in

children is antagonized much faster and by much smaller

doses of anticholinesterases as compared to adults. Bothcholinesterase and pseudocholinesterase levels are reduced

in premature and term newborns.14 Adult levels are not

reached until one year of age. Inspite of the reduced

pseudocholinesterase levels, newborns are more resistant to

succinylcholine than adults are.

Local anaesthetic agents2

Local anaesthetics are used in children as topical

application or subcutaneous injection for needle procedures,

neuraxial blockade and peripheral nerve blockade. Uptake

into the nerves from perineural injection sites competes

with uptake into the central circulation. Direct measurement

of intra-neural concentration of radiolabelled anaestheticsin animal models indicate that less than 2-3% of an injected

dose ever enters the nerve and within 30 minutes of injection

more than 90% of an injected dose is taken up into the

systemic circulation. This is significant as all the

aminoamides including bupivacaine, levobupivacaine,

lignocaine and ropivacaine show diminished clearance in

neonates with maturation over the first 3-8 months of age.

Limited information suggests that the aminoesters, which

are metabolized by plasma esterases, have a very rapid

clearance even in neonates.

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Most drugs in pediatric dosing are usually on a

weight scaled basis. However, it has been found that

neonates have a shorter block duration and require a much

larger (four fold) weight scaled dose to achieve a similardermatomal levels when given a subarachnoid block or

achieve a similar peripheral nerve block as an adult. This

is not only due to a higher weight scaled volume of CSF

but there may also be age related differences in

pharmacodynamic responses, myelination, spacing of nodes

of ranvier, tissue barrier and other factors. Another important

factor is the dependence of minimal blocking concentration

on the length of nerve exposed to local anaesthetic. The

minimal blocking concentration decreases dramatically as

the length of nerve exposed to the local anaesthetic is

increased as shown in the figure 3a. Hence the absolute

dose of local anaesthetic required to block a nerve shoulddepend on the length of the nerve exposed to drug and

should be only weakly dependent on body size (figure 3b).

Conversely if adult and infant nerves receive the same

weight scaled dose (figure 3c), other factors being equal,

the adult nerve will have a longer duration nerve blockade

than the infant nerve.

be so narrow that maximum safe infusion rates of the aminoamides are too low to provide sole analgesia for mostmajor surgery of the thorax, abdomen or pelvis. Thus, infants

require higher weight scaled infusion rates than adults toachieve blockade but they can safely receive only a lowerweight scaled infusion rate than adults from the viewpointof toxicity. To provide adequate safe analgesia other agentssuch as opioids, clonidine or ketamine may be used in theepidural space to provide synergistic analgesia. Anotherapproach is to use single stereoisomer like ropivacaine and

levobupivacaine to decrease the likelihood of cardiac toxicity.

Inhalational agents5

The use of inhalational anaesthetics in children hasbeen the mainstay of anaesthetic practice for the last 150years. The potency of an inhaled anaesthetic is determined

by its minimum alveolar concentration (MAC). Therequirement of inhalational agents varies inversely withage. MAC is lower with preterm infants than in terminfants and increases with post conceptual age. Age relatedchanges in MAC imply that the same alveolar concentrationwill produce different levels of anaesthesia in children ofdifferent ages.13

Factors affecting FE/F

I,that is, the ratio between

the end tidal anaesthetic concentration and the inspiredanaesthetic concentration, which is a measure of how rapidlygas equilibrates between lung and tissue, are inspiredanaesthetic concentration, blood gas partition coefficient

and cardiac output.5 Paediatric considerations of these willbe discussed in detail.

FIor inspired anaesthetic concentration The higher

the anaesthetic concentration the more quickly FE

movestoward F

I.

Changes in ventilation and FRC - The greater theminute ventilation, as in infants and children, the morerapid the rise occurs (assuming a constant cardiac output).

The smaller the FRC the faster the FE/F

Iincreases. The

FRC in infants is smaller than that of adults but tidalvolume per kg body weight is the same as that of adults.The more rapid respiratory rate, though, increases the minute

ventilation in the young.

Right to left shunting of blood - Which is oftenpresent in neonates and infants, slows induction of anaesthesiabecause in them the blood concentration of anaestheticsrises more slowly.

Blood/gas partition coefficients and anaestheticsolubility - The F

E/F

Iof an insoluble gas like sevoflurane or

nitrous oxide rises rapidly while with a more soluble gaslike halothane it rises more slowly. In general, however,inhaled anaesthetic agents are less soluble in the blood ofpaediatric patients. For example, the blood/gas partition

Minimumblocking

concentration

Fig. 3a

Infant nerve

Adult nerve

Infant nerve

Adult nerve

Fig. 3b : Fixed dose (mg) independent of age or body size

Fig. 3c : Weight scaled dosing (constant mgkg-1)

The implication of the above include the fact that

the therapeutic index of local anaesthetics in infants may

Length of nerve

exposed to local

anaesthetic

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coefficients of halothane and isoflurane are 18% lower inneonates than in young adults (20-40%) and in children(1-7 years) are 12% less than in young adults. This difference,

which accounts for the more rapid rise of FE/FI in neonates,is due in part to lower albumin concentration.

During anaesthesia, the blood gas partition coefficientcan drop by approximately 10% due to haemodilution withcrystalloid and reduction in haematocrit.

Blood tissue partition - Anaesthetic solubility inbrain, heart and liver increase by approximately 50%between the newborn period and middle age and is probablydue to a decrease in water and an increase in lipid contentwith age.

Partial pressure of anaesthetics - Because the blood

flow per unit tissue mass is greater in neonates the levelof anaesthetic in the tissue increases more rapidly and theinduction of anaesthesia is more rapid

Increased cardiac output reduces the rate of rise ofalveolar concentration of anaesthetic because moreanaesthetic is removed per unit of time. The cardiac outputof neonates per kilogram is normally twice that of adults.However F

E/F

Irises more rapidly because much of the

cardiac output of neonates and infants directed to the vesselrich tissues (VRG), which then get saturated sooner.

Specifics

The CNS - Drugs can penetrate the CNS of neonates

more easily than that of adults either because the neonatalblood brain barrier is more permeable or because cerebralblood flow is slower and the drugs have a longer time todissociate from plasma proteins. The blood brain barrier inneonates is also more easily disrupted by hypoxia and acidosis

than it is in adults.5

The cardiovascular system - The incidence ofbradycardia, hypotension and cardiac arrest during inductionis higher in infants and small children than in adults. Thishas been attributed to an increased sensitivity of the CVSto potent agents.15,16

Induction characteristics - The most commonly usedinduction agent in pediatrics is halothane and more recently,

sevoflurane. The primary criterion to assure a rapidinduction is the wash in curve in the first minute or twoof anaesthesia.17 During the first couple of minutes of aninhalational induction, the alveolar-to-inspired concentrationratio of these potent inhaled anaesthetics reaches to about0.33. When the wash in of halothane and sevoflurane were

compared in the first few minutes 5% inspired halothaneachieved an alveolar concentration of 1.65% or 1.65 MAC,18

whereas 8% sevoflurane achieved a concentration of 2.64,just in excess of 1 MAC. Although both anaesthetics providefor a rapid loss of eyelash reflex (1/3 faster with 8%

sevoflurane than 5% halothane with single breath induction19

the depth of anaesthesia achieved with sevoflurane is lessthan that of halothane because of the reduced MAC multiple

in sevoflurane. It is also suggested that if sevoflurane isintroduced slowly as is the practice with halothane aprotracted excitement phase is seen before an adequatedepth of anaesthesia is achieved.20 Lerman therefore suggestsbased on the above observations, an increase to an inspiredconcentration of 8% sevoflurane as quickly as possible.

Metabolism - Inhalational agents are apparentlymetabolized by paediatric patients to a lesser degree thanadults.5 Infants can biotransform halothane but do so to alesser extent than adults. Cited as further evidence for thisis the low incidence of halothane induced hepatitis in thepaediatric age group despite repeated doses of halothane.

5% of inhaled sevoflurane is metabolized in vivoproducing increased levels of fluoride.20 However, thelimited metabolism of sevoflurane within the kidney doesnot provide sufficient fluoride to inhibit tubular reabsorptionto any extent. This together with its rapid washoutexplains the lack of nephrotoxicity with sevofluranecompared with methoxyflurane. Other degradationcompounds have been seen in vitro, but are not ofsignificance. What is important, though, are the isolatedreports of extreme heat and flammability occurring inbreathing circuits using desiccated carbon-dioxide absorbent

Emergence delirium is common with inhalational

agents, more so with sevoflurane than with halothane.21Pain is a confounding factor in the study of emergencedelirium and the lack of understanding ED is the lack of

a specific tool to assess it. A recently developed scale21

may help clarify this.

References

1. Meretoja O. Update on muscle relaxants. Pediatr Anaesth

2004; 14: 384-6.

2. Berde C. Local anaesthetics in infants and children: an update.

Pediatr Anaesth 2004; 14: 387-393.

3. Kearns GL, Susan M, Abdul Rahman et al. Developmental

Pharmacology Drug disposition, action and therapy in

infants and children. N Engl J Med 2003; 349: 1157-67.

4. Stoelting RK. Pharmacology and Physiology in anaesthetic

practice. 3 rd edn. Lippincott Raven. Philadelphia New York

1999: 1-35.

5. Gregory GA. Pharmacology. In: George A Gregory. Pediatric

Anaesthesia, Churchill Livingstone, New York 1994: 13-47.

6. Jonmarker C, Westrin P, Larsson S, Werner O. Thiopental

requirements for induction of anaesthesia in children.

Anesthesiology 1987; 67: 104.

7. Lake CL. Paediatric Cardiac Anaesthesia, East Narwalk, Conn

1988, Appleton and Lange.

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8. Murat I, Billard V, Vernois J et al. Pharmacokinetics of

propofol after a single dose in children aged 1-3 years with

minor burns. Anesthesiology 1996; 84: 526-32.

9. Way WL, Costley EC, Way EL. Respiratory sensitivity of thenewborn infant to meperidine and morphine. Clinical Pharmacol

Ther 1965; 6: 454.

10.Lynn AM, Slattery JT. Morphine pharmacokinetics in early

infancy. Anesthesiology 1987; 66: 136.

11. Collins G, Koren G, Crean P et al. Fentanyl pharmacokinetics

and haemodynamic effects in preterm infants of ligation of

patent ductus arteriosus. Anaesth Analg. 1985; 64: 1078.

12. Cook DR, Fischer CG. Neuromuscular blocking effects of

succinylcholine in infants and children. Anesthesiology 1975;

42: 662.

13. Gormley SMC, Crean PM. Basic principles of anaesthesia for

neonates and infants. Br J Anaesth CEPD reviews 2001; 5:

130-133.

14. Wood Wood. Drugs and anaesthesia. Pharmacology for

Anaesthesiologists.2nd edn. Williams and Wilkins Baltimore,

Maryland USA. 1990: 32-33.

15.Friesen RH, Lichtor JL. Cardiovascular depression during

halothane anaesthesia in infants: a study of three induction

techniques. Anaesth Analg 1982; 61: 42.

16.Friesen RH, Lichtor JL. Cardiovascular effects of inhalationalinduction with isoflurane in infants. Anaesth Analg 1983; 62:

411.

17. Yasuda N, Lockhart SH, Eger EI II et al. Comparison of

kinetics of sevoflurane and isoflurane in humans. Anaesth

Analg 1991; 72: 316-324.

18. Gregory GA, Eger EI II, Munson ES. The relationship between

age and halothane requirement in man. Anesthesiology 1969;

30: 488-491.

19.Agnor R, Sikich N, Lerman J. Single breath vital capacity

rapid inhalation inductions in children: 8% sevoflurane versus

5% halothane. Anesthesiology 1998; 89: 49-54.

20.Lerman J. Inhalational anaesthetics. Pediatr Anaesth 2004;

14: 380-383.21. Cravero J, Surgenor S, Whalen K. Emergence agitation in

paediatric patients after sevoflurane anaesthesia and no surgery:

a comparison with halothane. Pediatr Anaesth 2000; 10:

419-424.

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19. N0396 NYMPHIA KAUL DELHI 9

20. N0403 MAJOR NITIN SHARMA DELHI

21. N0472 DR. N.D.MISRA SIKAR, (RAJ)

22. O0008 SUSMITA OOMMAN JABHALPUR

S.No ISANo NAME CITY

23. P0280 DR. DILIP KUMAR PAWAR NEW DELHI

24. R0012 DR M.VENKTA RAO HYDERABAD

25. S0938 DR VARSHA M. SHAH AHMEDABAD

26. S0991 DR SANGITA HASMUKHLAL SHAH NAVSARI

27. S1062 DR. NEMI KANT SHARMA JABALPUR

28. S1296 DR AJAY KUMAR SINHA LUCKNOW

29. S1415 MANTHA BALA TRIPURA SUNDARI JAYKAYPUR

30. S1892 DR. SHUBHANKAR GANGULY MUMBAI

31. S2198 DR SHIVANAND.N.V BELLARY

32. S2241 DR SUMA SIDDAVEERE GOWDA CHENNAI

33. S2317 DR SEEMA BHASKAR DESHMUKH AHMED NAGAR

34. S2417 DR G. SANTHANAM COIMBATORE

35. S2450 DR SANJEEV KUMAR VARANASI

36. T0093 DR S.K. THOMBRE PUNE

37. T0111 DR DINESH MAGANLAL THAKKER BOMBAY

38. T0285 DR. SHAH TUSHAR RAMESH BHAI RAJKOT

39. U0066 DR MRS.USHA JAIN TRIVANDRUM

40. V0267 DR MEET VERMA PATNA

41. V0276 DR N. VIVEKANANDAN BOMBAY

42. V0493 DR VADLAPUDI GOVINDARAJULU CHENNAI

43. V0571 DR VED PRAKASH KANPUR (U.P.)

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