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Current Anaesthesia & Critical Care (2004) 15, 302–308

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FOCUS ON: PAEDIATRICS

General principles of neonatal anaesthesia

Hannah Kinga,�, Peter D. Bookerb

aDepartment of Paediatric Anaesthesia, Royal Liverpool Children’s Hospital, Eaton Road,Liverpool L12 2AP, UKbDepartment of Paediatric Anaesthesia, University of Liverpool, Royal Liverpool Children’s Hospital,Eaton Road, Liverpool L12 2AP, UK

Summary Paediatric anaesthesia has long been recognised as a sub-specialtywithin anaesthesia and anaesthesia for the neonate is a further branch to thisspecialization. A thorough understanding of the neonate’s airway anatomy,physiology as well as pharmacology is required before the anaesthetic managementof the neonatal surgical condition can be considered.& 2004 Elsevier Ltd. All rights reserved.

Introduction

Neonatal life, defined as the first 28 days afterbirth, is characterized by rapid development andmaturation of many essential physiological sys-tems. Many of these changes are the result of thenewborn baby having the capacity to adapt rapidlyto the change from intrauterine to extrauterinelife, and of the persistence into neonatal life ofsome of the mechanisms whereby this is achieved.

It is not surprising therefore, that within the sub-specialty of paediatric anaesthesia, the provision ofsafe peri-operative care for the neonate requiringmajor surgery frequently offers the greatest in-tellectual and practical challenges. All neonatesshould be anaesthetised only in centres that havethe resources and expertise necessary to care forthem throughout the peri-operative period.

ee front matter & 2004 Elsevier Ltd. All rights reservacc.2004.09.002

ng author.ess: hannahking@henry.pau.clara.co.uk (H. King).

A thorough understanding of neonatal pathophy-siology is required before the anaesthetic manage-ment of neonatal surgical conditions can beconsidered. Many of the physiological differencesbetween the neonate and the adult are a reflectionof the relative differences in their basal metabolicrate; oxygen consumption in the term neonate is6ml kg�1min�1 compared to only 3ml kg�1min�1 inthe adult. This increased oxygen demand has to bemet by corresponding increases in alveolar ventila-tion and cardiac output. The reasons for this highmetabolic rate include the rapid tissue turnoverrelating to growth and development, and anincreased requirement for non-shivering thermo-genesis.

Respiratory anatomy and physiology

The small nasal passages account for between 30%and 50% of the total airway resistance in neonates.

ed.

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General principles of neonatal anaesthesia 303

The narrowest portion of the nasal airway, about1 cm proximal to the alar rim, has a cross-sectionalarea of about 20mm2. Therefore, even a smallamount of swelling in this area causes a dispropor-tionate and detrimental effect on the work ofbreathing. Hence, it is not surprising that aproportion of young infants who develop upperrespiratory tract infections that result in partialobstruction of their nasal passages develop respira-tory distress. Moreover, young infants up to aboutsix months of age are preferential nasal breathers.Studies suggest that up to 50% of neonates areunable to breathe through their mouths exceptwhen crying. At present, we are unable to predictwhich particular babies are able to switch to oralbreathing and at what age.

In contrast to adolescents and adults, thenarrowest part of the infant’s airway is not at thevocal cords, but at the cricoid ring. Hence,insertion of a tube that easily passes through thevocal cords, but encounters resistance in the sub-glottic area may result in the development ofmucosal oedema and postextubation stridor. Thiscan be prevented by using an uncuffed endotra-cheal tube of the correct size, which will produce asmall but audible leak at an airway pressure ofabout 20–25 cm H2O.

Several anatomical factors result in the need fora modified technique in laryngoscopy in order toobtain a good view and an atraumatic intubation.These include a large tongue; a larynx that lies atthe level of C3/4 compared to C4/5 in the adult andwhich is tilted anteriorly; an epiglottis that islonger and omega shaped; and vocal cords thathave a lower anterior attachment than posterior. Toprepare for laryngoscopy, the neonate’s headshould be placed in a neutral or slightly flexedposition, as hyperextension results in an acuteangle between the larynx and the trachea. Duringbag and mask ventilation, the anaesthetist shouldlimit all finger contact to the bony prominences toprevent obstruction of the airway by externalcompression. A straight blade, such as a Wisconsin(size 0 for preterm and size 1 for term neonates),should be passed into the oesophagus and then

Table 1 Neonatal endotracheal tube sizes.

Weight (kg) Internaldiameter (mm)

Oral length (cm)

o2 2.5–3.0 92–3 3.0 103–3.5 3.5 12

withdrawn slowly; this manoeuvre will lift theepiglottis anteriorly and allow visualization of thelarynx.

The distance from the vocal cords to the carina interm neonates is approximately 5 cm; the tracheallength, the distance from the first tracheal ring tothe carina, is about 4.1 cm. Hence, to ensure thatthe endotracheal tube is secured such that its tip isat mid-trachea level means that it needs to beinserted about 2.5 cm past the cords. Table 1contains guidelines for the size of endotrachealtube required for neonates of various weights andthe corresponding insertion length.

All inspired gases must be humidified, as anyreduction in the calibre of the endotracheal tubeby dried secretions will result in increased airwayresistance and the work of breathing. This can beavoided simply by use of a heat moisture exchangedevice (HME); these are cheap and easy to use andincorporate an outlet port for a capnograph. Thepotential disadvantages of an increase in deadspace (about 10ml) and resistance to flow (typi-cally o1 cm H2O at a 3 lmin�1 flow rate even whenmoist), only become significant during spontaneousrespiration, which in any event should not beallowed for prolonged periods in the intubatedneonate.

The respiratory system is not fully developed atbirth even in the term neonate and postnatalmaturation continues for a significant time.Although by 20–27 weeks gestation lung acinarhave formed, several types of epithelial cells canbe differentiated, and the air-blood barrier is thinenough to support gas exchange; true alveolidevelop only after about 36 weeks gestation. Aterm newborn has approximately 50 million alveoli.The remaining 85% of the eventual 300 millionalveoli develop after birth, the vast majority withinthe first two years of life.

Pulmonary surfactant is a mixture of phospholi-pids (90%), particularly phosphatidylcholine, andapoproteins (10%), which act to reduce surfacetension at the air–liquid interface in the alveolus,thereby preventing collapse of lung parenchyma atthe end of expiration. Type II alveolar cellssynthesize and secrete surfactant from 23 to 24weeks gestation. In preterm newborns, a deficiencyof surfactant is a major factor in the developmentof neonatal respiratory distress syndrome (RDS).The use of exogenous surfactant in the manage-ment of RDS was introduced in the 1980s and itsclinical efficacy has been demonstrated in numer-ous trials and meta-analyses. A short course ofexogenous glucocorticoids administered to motherswithin seven days of premature delivery results insignificant improvements in the clinical outcomes

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of preterm infants. Maternal glucocorticoid therapyresults in increased synthesis of surfactant lipids,accelerated lung maturation, and a resultantdecrease in the incidence and severity of RDS.

The high basal metabolic rate and hence oxygendemand of the neonate is met in part by alveolarventilation (VA) being twice that of the adult(100–150ml kg�1min�1 vs. 60ml kg�1min�1). Thishigh minute volume is achieved by increasing therespiratory rate rather than the tidal volume,the most energy efficient method of increasingVA. The diaphragm is the major muscle of respira-tion in the neonate. Early studies suggested thatthe neonatal diaphragm was particularly suscepti-ble to fatigue; however, more recent experimentalwork suggests the exact opposite. Although theoxidative capacity of adult diaphragm is signifi-cantly greater than that of the neonate, it is moresusceptible to fatigue during repetitive isometricactivation. Clinically, nonetheless, the high basalminute volume of the neonate does not allow a largerespiratory reserve capacity. Moreover, downwardmovement of the diaphragm during inspiration islimited by the presence of a relatively large liver; inresponse to respiratory stimulation, the neonate hasa restricted ability to increase tidal volume.

The functional residual capacity (FRC) of aneonate, measured on a ml per kg basis, is similarto that of an adult. As a result, the VA/FRC ratio is5:1 in the neonate compared to 1.5:1 in the adult.This high ratio is one of the reasons why gasinductions are more rapid in the very young, but italso accounts for the more rapid depletion ofoxygen reserves and rate of desaturation.

Neonates have an imbalance between a rela-tively low outward recoil of their chest wall andnormal inward recoil, which means that they areprone to airway collapse. An awake, spontaneouslybreathing neonate will maintain its FRC by activemeasures including laryngeal braking, the initiationof inspiration before the end of passive expiration(intrinsic PEEP), and persistent inspiratory activityof the inspiratory muscles throughout the respira-tory cycle. These active mechanisms are lost duringanaesthesia and result in a fall in FRC, airwayclosure, atelectasis and ventilation/perfusionmismatch.

Periodic breathing and episodes of apnoea arerelatively common in neonates and are related toimmature cardiorespiratory control. Apnoea epi-sodes, which are defined as cessation of breathingfor 415 s, can be further classified as central(absence of respiratory effort), obstructive (noairflow despite respiratory effort), and mixed.Hence, methods of detection that detect chestwall movement, such as impedance pneumography,

may not detect all apnoeic episodes. Apnoeas mayoccur as an isolated event but are usually asso-ciated with bradycardia and desaturation. Theincidence of postoperative apnoea is 20–30% inotherwise healthy preterm infants undergoinghernia repair under general anaesthesia. Infantsthat develop postoperative apnoeas do so within12 h of surgery; they may persist for up to 48 h. Theincidence of apnoea is inversely related to gesta-tional age and becomes less frequent when post-conceptional age is 443 weeks, but may occur aslate as 60 weeks postconceptional age.

Cardiovascular physiology

The fetal circulation is characterized by a highpulmonary vascular resistance (PVR), low systemicvascular resistance (SVR) and left-to-right shuntingthrough the foramen ovale and ductus arteriosus.At birth, following the clamping of the cord, theSVR increases. Onset of respiration results inexpansion of the lungs, oxygenation of the alveoli,and a resultant fall in the PVR. Functional closureof the foramen ovale occurs due to increased leftatrial pressure as a result of increased blood flow tothe lungs. Although anatomical closure can occur asearly as three months of age, the channel remainsprobe patent in 50% of children up to five years ofage, and persists in about 30% of adults. Suchpatency may become functionally significant if, atany time, right atrial pressure exceeds left atrialpressure. Similarly, the ductus arteriosus function-ally closes secondary to a high PaO2; anatomicalclosure usually occurs between 4 and 8 weeks ofage. Any stimulus, such as hypoxia or acidosis, thatcauses an increase in PVR during the neonatalperiod may allow these two potential channels toreopen, resulting in right-to-left shunting andincreasing hypoxia.

The increased oxygen demands of the neonatehave to be met by an increased cardiac output: thenormal cardiac output during the neonatal period isapproximately 180ml kg�1min�1, which is, relativeto body weight, twice that of an adult. Theneonatal myocardium contains more non-contrac-tile elements and disorganized myofibrils comparedto the adult myocardium; as a result, it is lesscompliant and less able to generate force. It is alsomore dependent on extracellular calcium forcontraction because of an immature sarcoplasmicreticulum and T-tubular system.

Neonates exhibit a higher basal level of contrac-tility than in later childhood, partially related tothe relatively low afterload experienced by the

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immature heart, and partially related to increasedsympathetic activity; adrenoceptor downregulationis only gradually acquired during postnatal devel-opment. The neonate is particularly dependent ona high heart rate to maintain its normal level ofcontractility. Cardiac output in neonates is mainlyaltered by changes in heart rate and not by changesin stroke volume, though they are able to regulatecardiac output by changing stroke volume to agreater extent than is often presumed.

Renal and hepatic physiology

Postconceptional age is the most important vari-able affecting renal function in the neonate.Tubular function is relatively immature at birthand the glomerular filtration rate (GFR) is approxi-mately 30% that of an adult. During the neonatalperiod, there is an abrupt increase in GFR andtubular function and this improvement continuesuntil about five months of age when adult valuesare reached.

Neonates produce hypotonic urine as a result oftheir limited concentrating ability, related to theirpoorly developed medullary concentration gradientand reduced responsiveness to antidiuretic hor-mone. The ability to handle a water load is alsolimited, especially in premature infants, because ofthe low GFR during the first few months of life. Thismakes them susceptible to hyponatraemia follow-ing administration of excessive volumes of hypo-tonic fluids. Renal excretion of drugs occurspredominantly by glomerular filtration and tubularsecretion. Hence, drugs such as aminoglycosides,which are excreted unchanged by the kidneys, haveprolonged serum half-lives.

At birth, most hepatic enzyme systems for drugmetabolism are developed but inactive. The liverundergoes rapid maturation after birth regardlessof the extent of prematurity: conjugation reactionsdevelop from minimal levels to almost adult levelswithin two weeks of birth in most infants. Duringthis time conjugation of bilirubin is often inade-quate, resulting in a physiological unconjugatedhyperbilirubinaemia. The neonatal liver, particu-larly in the preterm infant, has limited glycogenreserves, resulting in the newborn’s tendency tohypoglycaemia.

The concentration of albumin is near adult levelsin the term neonate, though may be markedlydecreased in preterm infants. In contrast, theconcentrations of plasma proteins involved incoagulation are usually low in the newborn, thoughthey rapidly increase within a few days. Synthesis

of vitamin K dependent clotting factors is exacer-bated by the paucity of vitamin K synthesis byenteric bacteria. The routine parenteral adminis-tration of vitamin K helps to prevent ‘haemorrhagicdisease of the newborn’: it takes about six weeksfor the increasing mass of enteric bacteria toproduce sufficient vitamin K.

Thermoregulation

Neonates show greater fluctuations in body tem-perature than adults. This is due to their largesurface area to volume ratio and relatively smallinsulating body shell. The neonate’s capacity togenerate heat is comparable to adults, when themetabolic rate is related to body mass, but it isinsufficient to compensate for heat loss in as wide arange of ambient temperatures. This results in areduction in the tolerated ambient temperaturerange. The full term neonate uses maximumthermogenesis to maintain a stable body tempera-ture in an ambient temperature of 23 1C whereas anadult can maintain thermal balance in tempera-tures between 0 1C and 5 1C. The thermoneutralzone is defined as ‘‘the range of ambient tempera-ture at which metabolic rate is a minimum, andwithin which the temperature regulation isachieved by control of sensible heat loss, that is,without regulatory changes in metabolic heatproduction or evaporative heat loss’’. In the nakedfull-term newborn infant the lower limit of thisrange is 32–35 1C.

Non-shivering themogenesis in brown adiposetissue is the major mechanism of heat productionduring the first few months of life. Brown fat isspecialized tissue located in the posterior of theneck, along the interscapular and vertebral areas,and surrounding the kidneys and adrenal glands.Thermogenesis via triglyceride hydrolysis is stimu-lated via nor-epinephrine acting on adrenergic b-receptors. Metabolic heat production can increaseup to 2.5-fold during cold stress. Shivering is a lesseconomical form of heat production but does occurin severely hypothermic neonates.

Neonates also have well-developed vasomotorresponses to environmental temperature changes;sympathetic tone increases in response to coldresulting in peripheral vasoconstriction and de-creased heat transfer to the outer core. Theneonate’s response to heat stress is peripheralvasodilation and sympathetically activated sweat-ing. Although the neonatal density of sweat glandsis approximately six times that of the adult, the

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peak response is only 30% that of the adult;maturation of function is linked to gestational age.

The neonate’s thermoregulatory mechanisms areabolished under anaesthesia and this makes themvulnerable to peri-operative hypothermia. If sig-nificant hypothermia continues into the postopera-tive period it will result in increased oxygenconsumption when the thermoregulatory reflexesreturn and an associated increase in morbidity.Simple measures including warm air convectionblankets, warmed fluids and humidification ofinspired gases will usually suffice to maintain aneonate’s core temperature during major surgery.

Anaesthetic drugs

The pharmacology of anaesthetic drugs in neonatesdiffers from that in older children because ofdifferences in body size, composition, and imma-turity of several organ systems. Water constitutesabout 75% by weight of a term neonate, comparedto about 57% in the adult, resulting in a proportio-nately larger extracellular volume and volume ofdistribution for water-soluble drugs. In contrast,fat constitutes only about 15% of body weight in theneonate, rapidly increasing to about 30% by sixmonths of age, resulting in a smaller volume ofdistribution for lipophilic drugs. As already de-scribed, the immaturity of the renal and hepaticsystems further alters drug metabolism and theincreased permeability of the blood brain barrierresults in an increased sensitivity to some centrallyacting drugs.

Inhalational anaesthetics

Sevoflurane and isoflurane are the most commonlyused inhalational anaesthetics in neonatal anaes-thetic practice. Sevoflurane possesses near idealcharacteristics as an induction agent, though itscost prohibits its use for prolonged maintenance ofanaesthesia. Isoflurane should not be used toinduce anaesthesia, as its pungency causesbreath-holding, and laryngospasm; however, it isentirely suitable for maintaining anaesthesia. Up-take and elimination of both these agents is fasterin infants compared to adults. Several factors areresponsible for this difference, including the highVA/FRC ratio in the neonate; the greater fraction ofthe neonatal cardiac output being distributed tovessel rich tissues; and lower blood/gas and blood/tissue partition coefficients.

The minimum alveolar concentration (MAC) ofvolatile anaesthetic agents changes with age; in theneonatal period it increases with gestational age,and then reaches a peak during infancy, beforedecreasing throughout childhood and adulthood. Inneonates, the MAC values are 25% less than in olderinfants; at these values the haemodynamic re-sponses are similar to those seen in older infantsand children.

Intravenous anaesthetics

Thiopentone is the most commonly used intrave-nous induction agent in neonates, as propofol is notlicensed for induction or maintenance of anaes-thesia in the very young. The ED50 for inductionagents is the dose that prevents a response in 50%of patients; a concept similar to MAC. The ED50 forthiopentone in neonates is 3.4mg kg�1 compared to6.3mg kg�1 in infants between 1 and 6 months ofage. The reasons for this large age-related differ-ence include an increase in the free fraction of thedrug, the increased permeability of the blood-brainbarrier, and decreased anaesthetic requirements ofthe neonate due to immature brain function.

Opioids

Neonates have increased and variable sensitivity toopioids, particularly with regard to their respira-tory depressive effects. Appropriate and contin-uous monitoring is mandatory for all neonatesreceiving opioid therapy.

Morphine is the most commonly used opioid forperi-operative analgesia in neonates. Morphine isconjugated to the active metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide(M6G) by glucuronidation; in neonates, the M3G/M6G ratio is about 5, compared to about 1 inchildren and adults. Clearances of the renallyexcreted metabolites are not significantly affectedby postnatal age. Clearance of morphine is about10mlmin�1 kg�1 in the term neonate; adult valuesof morphine clearance (24mlmin�1 kg�1) arereached by about six months of age. Hence, asingle dose of morphine given to a neonate at theonset of surgery will have a prolonged duration ofaction. Similarly, accumulation of morphine isinevitable during an infusion given in the post-operative period, and repeated assessments ofsedation and analgesia requirements, with appro-priate adjustments of infusion rate, are required toavoid overdose.

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Fentanyl is a potent opioid that offers relativehaemodynamic stability. It is highly lipid solubleand is cleared by hepatic dealkylation and hydro-xylation; clearance of fentanyl increases withpostconceptional age and birth weight. Clearanceof fentanyl in neonates less than one-weekold is about 7ml kg�1min�1, compared to24ml kg�1min�1 at three weeks of age. Neonateswith conditions that result in increased intra-abdominal pressure, such as after gastroschisisrepair, have a further reduction in clearance,probably related to the associated decrease inhepatic blood flow.

Remifentanil hydrochloride undergoes rapid hy-drolysis by plasma and tissue esterases. In contrastto all other opioids, clearance in neonates(91ml kg�1min�1) is significantly higher than clear-ance in adults (47ml kg�1min�1). Volume of dis-tribution is relatively high in infants, butnonetheless, recovery time after a prolongedinfusion does not change significantly with age ordevelopment. Bolus doses cause hypotension, andthis drug should always be given by continuousinfusion; it does not require a loading dose.

Muscle relaxants and antagonists

Although both depolarizing and non-depolarizingmuscle relaxants can be used to facilitate trachealintubation in neonates, most experienced paedia-tric anaesthetists tend to use non-depolarizingrelaxants in neonates, even when there is apotential risk of aspiration. The advantages ofrapid onset and offset of action of succinylcholineseen in older children are less obvious in neonates.Most neonatal surgery is relatively lengthy induration, and non-depolarizing relaxants will

Table 2 Recommended initial dose for commonly used i

Drug Dose Comments

Thiopentone 2–3mg kg�1 Do not repeatMorphine 25–50mcg kg�1 Duration of act

postoperativelyFentanyl 3–5mcg kg�1 Duration of act

postoperativelyAtracurium 0.5mg kg�1 Duration of act

age groupRocuronium 0.6mg kg�1 Duration of actVecuronium 70mcg kg�1 Onset times mo

times are longeNeostigmine 50mcg kg�1 Do not give unAtropine 20mcg kg�1 Aim for heart r

always be needed. Aspiration problems are extre-mely rare in neonates, particularly if the stomachis emptied using a nasogastric tube prior toinduction. Onset of action of non-depolarizingrelaxants such as atracurium or rocuronium isrelatively fast in neonates, particularly if a largedose is used (Table 2). Careful pre-operativeassessment of the airway is required before sucha technique is used.

The intermediate acting non-depolarizingmuscle relaxants such as atracurium and rocuro-nium do not normally accumulate after repeateddosing. Atracurium is particularly useful in theneonate as it breaks down spontaneously atbody pH and temperature in a process known asHofmann elimination, which is unaffected byhepatic or renal immaturity. The potency ofvecuronium shows more variation with age thanother muscle relaxants. The ED50 values are 40%less in infants than children, and the dose should bereduced accordingly (Table 2). The action of non-depolarizing muscle relaxants should be reversed atthe end of the procedure if the neonate is to beextubated.

Fluid and electrolyte balance

Normal saline or Ringer’s lactate solution is equallyeffective to 5% albumin in the treatment ofhypotensive, preterm or term neonates. At pre-sent, there is little evidence to suggest that humanalbumin solution has any particular advantagesover other fluids as a plasma expander, particularlythe newer synthetic colloids, unless plasma albu-min concentrations are very low. During majorsurgical procedures, blood loss should be measuredby weighing swabs, or central venous pressureshould be monitored. Once blood loss exceeds 10%

ntravenous drugs.

dose. Avoid in sick or hypovolaemic neonatesion 46 h. Apnoea monitor and oximeter required

ion 44 h. Apnoea monitor and oximeter required

ion 30–40min. Histamine release not a problem in this

ion 45min. Monitor effect if further doses requiredre rapid in infants compared to children but recoveryrtil clinical signs of recovery from neuromuscular blockate 4120 and o160

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of total blood volume, blood products should betransfused. Dextrose-containing solutions shouldnot be used as plasma expanders. However, thereremains a concern that a proportion of neonatesmay become hypoglycaemic if not given a constantinfusion of a dextrose-containing solution. Neo-nates at particular risk include those o48 h old,preterm, or born to diabetic mothers. A practicalcompromise that appears to prevent hypoglycae-mia, while avoiding hyperglycaemia, is to uselactated Ringer’s solution containing a low concen-tration of dextrose (0.9–2.5%). Maintenance fluidsshould be infused at about 4ml kg�1 h�1; electro-lytes, glucose and haematocrit should be checkedregularly.

Further reading

1. Hackman PS. Recognizing and understanding the cold-stressed term infant. Neonatal Network 2001;20(8):35–41.

2. Beath SV. Hepatic function and physiology in the newborn.Semin Neonatol 2003;8(5):337–46.

3. Givan DC. Physiology of breathing and related pathologicalprocesses in infants. Semin Pediatr Neurol2003;10(4):271–80.

4. Pierro A. Metabolism and nutritional support in the surgicalneonate. J Pediatr Surg 2002;37(6):811–22.

5. Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH.Developmental pharmacokinetics of morphine and its meta-bolites in neonates, infants and young children. Br J Anaesth2004;92(2):208–17.

6. Meakin GH. Recent advances in myorelaxant therapy.Paediatr Anaesth 2001;11(5):523–31.