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Current Anaesthesia & Critical Care (2004) 15, 302308

www.elsevier.com/locate/cacc

FOCUS ON: PAEDIATRICS

General principles of neonatal anaesthesia


Hannah Kinga,, Peter D. Bookerb
a

Department of Paediatric Anaesthesia, Royal Liverpool Childrens Hospital, Eaton Road, Liverpool L12 2AP, UK b Department of Paediatric Anaesthesia, University of Liverpool, Royal Liverpool Childrens Hospital, Eaton Road, Liverpool L12 2AP, UK

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

Introduction
Neonatal life, dened as the rst 28 days after birth, is characterized by rapid development and maturation of many essential physiological systems. Many of these changes are the result of the newborn baby having the capacity to adapt rapidly to the change from intrauterine to extrauterine life, and of the persistence into neonatal life of some of the mechanisms whereby this is achieved. It is not surprising therefore, that within the subspecialty of paediatric anaesthesia, the provision of safe peri-operative care for the neonate requiring major surgery frequently offers the greatest intellectual and practical challenges. All neonates should be anaesthetised only in centres that have the resources and expertise necessary to care for them throughout the peri-operative period.
Corresponding author.

A thorough understanding of neonatal pathophysiology is required before the anaesthetic management of neonatal surgical conditions can be considered. Many of the physiological differences between the neonate and the adult are a reection of the relative differences in their basal metabolic rate; oxygen consumption in the term neonate is 6 ml kg1 min1 compared to only 3 ml kg1 min1 in the adult. This increased oxygen demand has to be met by corresponding increases in alveolar ventilation and cardiac output. The reasons for this high metabolic rate include the rapid tissue turnover relating to growth and development, and an increased requirement for non-shivering thermogenesis.

Respiratory anatomy and physiology


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

E-mail address: hannahking@henry.pau.clara.co.uk (H. King).

0953-7112/$ - see front matter & 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.cacc.2004.09.002

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General principles of neonatal anaesthesia The narrowest portion of the nasal airway, about 1 cm proximal to the alar rim, has a cross-sectional area of about 20 mm2. Therefore, even a small amount of swelling in this area causes a disproportionate and detrimental effect on the work of breathing. Hence, it is not surprising that a proportion of young infants who develop upper respiratory tract infections that result in partial obstruction of their nasal passages develop respiratory distress. Moreover, young infants up to about six months of age are preferential nasal breathers. Studies suggest that up to 50% of neonates are unable to breathe through their mouths except when crying. At present, we are unable to predict which particular babies are able to switch to oral breathing and at what age. In contrast to adolescents and adults, the narrowest part of the infants airway is not at the vocal cords, but at the cricoid ring. Hence, insertion of a tube that easily passes through the vocal cords, but encounters resistance in the subglottic area may result in the development of mucosal oedema and postextubation stridor. This can be prevented by using an uncuffed endotracheal tube of the correct size, which will produce a small but audible leak at an airway pressure of about 2025 cm H2O. Several anatomical factors result in the need for a modied technique in laryngoscopy in order to obtain a good view and an atraumatic intubation. These include a large tongue; a larynx that lies at the level of C3/4 compared to C4/5 in the adult and which is tilted anteriorly; an epiglottis that is longer and omega shaped; and vocal cords that have a lower anterior attachment than posterior. To prepare for laryngoscopy, the neonates head should be placed in a neutral or slightly exed position, as hyperextension results in an acute angle between the larynx and the trachea. During bag and mask ventilation, the anaesthetist should limit all nger contact to the bony prominences to prevent obstruction of the airway by external compression. 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 303 withdrawn slowly; this manoeuvre will lift the epiglottis anteriorly and allow visualization of the larynx. The distance from the vocal cords to the carina in term neonates is approximately 5 cm; the tracheal length, the distance from the rst tracheal ring to the carina, is about 4.1 cm. Hence, to ensure that the endotracheal tube is secured such that its tip is at mid-trachea level means that it needs to be inserted about 2.5 cm past the cords. Table 1 contains guidelines for the size of endotracheal tube required for neonates of various weights and the corresponding insertion length. All inspired gases must be humidied, as any reduction in the calibre of the endotracheal tube by dried secretions will result in increased airway resistance and the work of breathing. This can be avoided simply by use of a heat moisture exchange device (HME); these are cheap and easy to use and incorporate an outlet port for a capnograph. The potential disadvantages of an increase in dead space (about 10 ml) and resistance to ow (typically o1 cm H2O at a 3 l min1 ow rate even when moist), only become signicant during spontaneous respiration, which in any event should not be allowed for prolonged periods in the intubated neonate. The respiratory system is not fully developed at birth even in the term neonate and postnatal maturation continues for a signicant time. Although by 2027 weeks gestation lung acinar have formed, several types of epithelial cells can be differentiated, and the air-blood barrier is thin enough to support gas exchange; true alveoli develop only after about 36 weeks gestation. A term newborn has approximately 50 million alveoli. The remaining 85% of the eventual 300 million alveoli develop after birth, the vast majority within the rst two years of life. Pulmonary surfactant is a mixture of phospholipids (90%), particularly phosphatidylcholine, and apoproteins (10%), which act to reduce surface tension at the airliquid interface in the alveolus, thereby preventing collapse of lung parenchyma at the end of expiration. Type II alveolar cells synthesize and secrete surfactant from 23 to 24 weeks gestation. In preterm newborns, a deciency of surfactant is a major factor in the development of neonatal respiratory distress syndrome (RDS). The use of exogenous surfactant in the management of RDS was introduced in the 1980s and its clinical efcacy has been demonstrated in numerous trials and meta-analyses. A short course of exogenous glucocorticoids administered to mothers within seven days of premature delivery results in signicant improvements in the clinical outcomes

Table 1

Neonatal endotracheal tube sizes. Internal diameter (mm) 2.53.0 3.0 3.5 Oral length (cm) 9 10 12

Weight (kg) o2 23 33.5

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304 of preterm infants. Maternal glucocorticoid therapy results in increased synthesis of surfactant lipids, accelerated lung maturation, and a resultant decrease in the incidence and severity of RDS. The high basal metabolic rate and hence oxygen demand of the neonate is met in part by alveolar ventilation (VA) being twice that of the adult (100150 ml kg1 min1 vs. 60 ml kg1 min1). This high minute volume is achieved by increasing the respiratory rate rather than the tidal volume, the most energy efcient method of increasing VA. The diaphragm is the major muscle of respiration in the neonate. Early studies suggested that the neonatal diaphragm was particularly susceptible to fatigue; however, more recent experimental work suggests the exact opposite. Although the oxidative capacity of adult diaphragm is signicantly greater than that of the neonate, it is more susceptible to fatigue during repetitive isometric activation. Clinically, nonetheless, the high basal minute volume of the neonate does not allow a large respiratory reserve capacity. Moreover, downward movement of the diaphragm during inspiration is limited by the presence of a relatively large liver; in response to respiratory stimulation, the neonate has a restricted ability to increase tidal volume. The functional residual capacity (FRC) of a neonate, measured on a ml per kg basis, is similar to that of an adult. As a result, the VA/FRC ratio is 5:1 in the neonate compared to 1.5:1 in the adult. This high ratio is one of the reasons why gas inductions are more rapid in the very young, but it also accounts for the more rapid depletion of oxygen reserves and rate of desaturation. Neonates have an imbalance between a relatively low outward recoil of their chest wall and normal inward recoil, which means that they are prone to airway collapse. An awake, spontaneously breathing neonate will maintain its FRC by active measures including laryngeal braking, the initiation of inspiration before the end of passive expiration (intrinsic PEEP), and persistent inspiratory activity of the inspiratory muscles throughout the respiratory cycle. These active mechanisms are lost during anaesthesia and result in a fall in FRC, airway closure, atelectasis and ventilation/perfusion mismatch. Periodic breathing and episodes of apnoea are relatively common in neonates and are related to immature cardiorespiratory control. Apnoea episodes, which are dened as cessation of breathing for 415 s, can be further classied as central (absence of respiratory effort), obstructive (no airow despite respiratory effort), and mixed. Hence, methods of detection that detect chest wall movement, such as impedance pneumography, H. King, P.D. Booker may not detect all apnoeic episodes. Apnoeas may occur as an isolated event but are usually associated with bradycardia and desaturation. The incidence of postoperative apnoea is 2030% in otherwise healthy preterm infants undergoing hernia repair under general anaesthesia. Infants that develop postoperative apnoeas do so within 12 h of surgery; they may persist for up to 48 h. The incidence of apnoea is inversely related to gestational age and becomes less frequent when postconceptional age is 443 weeks, but may occur as late as 60 weeks postconceptional age.

Cardiovascular physiology
The fetal circulation is characterized by a high pulmonary vascular resistance (PVR), low systemic vascular resistance (SVR) and left-to-right shunting through the foramen ovale and ductus arteriosus. At birth, following the clamping of the cord, the SVR increases. Onset of respiration results in expansion of the lungs, oxygenation of the alveoli, and a resultant fall in the PVR. Functional closure of the foramen ovale occurs due to increased left atrial pressure as a result of increased blood ow to the lungs. Although anatomical closure can occur as early as three months of age, the channel remains probe patent in 50% of children up to ve years of age, and persists in about 30% of adults. Such patency may become functionally signicant if, at any time, right atrial pressure exceeds left atrial pressure. Similarly, the ductus arteriosus functionally closes secondary to a high PaO2; anatomical closure usually occurs between 4 and 8 weeks of age. Any stimulus, such as hypoxia or acidosis, that causes an increase in PVR during the neonatal period may allow these two potential channels to reopen, resulting in right-to-left shunting and increasing hypoxia. The increased oxygen demands of the neonate have to be met by an increased cardiac output: the normal cardiac output during the neonatal period is approximately 180 ml kg1 min1, which is, relative to body weight, twice that of an adult. The neonatal myocardium contains more non-contractile elements and disorganized myobrils compared to the adult myocardium; as a result, it is less compliant and less able to generate force. It is also more dependent on extracellular calcium for contraction because of an immature sarcoplasmic reticulum and T-tubular system. Neonates exhibit a higher basal level of contractility than in later childhood, partially related to the relatively low afterload experienced by the

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General principles of neonatal anaesthesia immature heart, and partially related to increased sympathetic activity; adrenoceptor downregulation is only gradually acquired during postnatal development. The neonate is particularly dependent on a high heart rate to maintain its normal level of contractility. Cardiac output in neonates is mainly altered by changes in heart rate and not by changes in stroke volume, though they are able to regulate cardiac output by changing stroke volume to a greater extent than is often presumed. 305 of vitamin K dependent clotting factors is exacerbated by the paucity of vitamin K synthesis by enteric bacteria. The routine parenteral administration of vitamin K helps to prevent haemorrhagic disease of the newborn: it takes about six weeks for the increasing mass of enteric bacteria to produce sufcient vitamin K.

Thermoregulation Renal and hepatic physiology


Postconceptional age is the most important variable affecting renal function in the neonate. Tubular function is relatively immature at birth and the glomerular ltration rate (GFR) is approximately 30% that of an adult. During the neonatal period, there is an abrupt increase in GFR and tubular function and this improvement continues until about ve months of age when adult values are reached. Neonates produce hypotonic urine as a result of their limited concentrating ability, related to their poorly developed medullary concentration gradient and reduced responsiveness to antidiuretic hormone. The ability to handle a water load is also limited, especially in premature infants, because of the low GFR during the rst few months of life. This makes them susceptible to hyponatraemia following administration of excessive volumes of hypotonic uids. Renal excretion of drugs occurs predominantly by glomerular ltration and tubular secretion. Hence, drugs such as aminoglycosides, which are excreted unchanged by the kidneys, have prolonged serum half-lives. At birth, most hepatic enzyme systems for drug metabolism are developed but inactive. The liver undergoes rapid maturation after birth regardless of the extent of prematurity: conjugation reactions develop from minimal levels to almost adult levels within two weeks of birth in most infants. During this time conjugation of bilirubin is often inadequate, resulting in a physiological unconjugated hyperbilirubinaemia. The neonatal liver, particularly in the preterm infant, has limited glycogen reserves, resulting in the newborns tendency to hypoglycaemia. The concentration of albumin is near adult levels in the term neonate, though may be markedly decreased in preterm infants. In contrast, the concentrations of plasma proteins involved in coagulation are usually low in the newborn, though they rapidly increase within a few days. Synthesis Neonates show greater uctuations in body temperature than adults. This is due to their large surface area to volume ratio and relatively small insulating body shell. The neonates capacity to generate heat is comparable to adults, when the metabolic rate is related to body mass, but it is insufcient to compensate for heat loss in as wide a range of ambient temperatures. This results in a reduction in the tolerated ambient temperature range. The full term neonate uses maximum thermogenesis to maintain a stable body temperature in an ambient temperature of 23 1C whereas an adult can maintain thermal balance in temperatures between 0 1C and 5 1C. The thermoneutral zone is dened as the range of ambient temperature at which metabolic rate is a minimum, and within which the temperature regulation is achieved by control of sensible heat loss, that is, without regulatory changes in metabolic heat production or evaporative heat loss. In the naked full-term newborn infant the lower limit of this range is 3235 1C. Non-shivering themogenesis in brown adipose tissue is the major mechanism of heat production during the rst few months of life. Brown fat is specialized tissue located in the posterior of the neck, along the interscapular and vertebral areas, and surrounding the kidneys and adrenal glands. Thermogenesis via triglyceride hydrolysis is stimulated via nor-epinephrine acting on adrenergic breceptors. Metabolic heat production can increase up to 2.5-fold during cold stress. Shivering is a less economical form of heat production but does occur in severely hypothermic neonates. Neonates also have well-developed vasomotor responses to environmental temperature changes; sympathetic tone increases in response to cold resulting in peripheral vasoconstriction and decreased heat transfer to the outer core. The neonates response to heat stress is peripheral vasodilation and sympathetically activated sweating. Although the neonatal density of sweat glands is approximately six times that of the adult, the

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306 peak response is only 30% that of the adult; maturation of function is linked to gestational age. The neonates thermoregulatory mechanisms are abolished under anaesthesia and this makes them vulnerable to peri-operative hypothermia. If signicant hypothermia continues into the postoperative period it will result in increased oxygen consumption when the thermoregulatory reexes return and an associated increase in morbidity. Simple measures including warm air convection blankets, warmed uids and humidication of inspired gases will usually sufce to maintain a neonates core temperature during major surgery. H. King, P.D. Booker The minimum alveolar concentration (MAC) of volatile anaesthetic agents changes with age; in the neonatal period it increases with gestational age, and then reaches a peak during infancy, before decreasing throughout childhood and adulthood. In neonates, the MAC values are 25% less than in older infants; at these values the haemodynamic responses are similar to those seen in older infants and children.

Intravenous anaesthetics
Thiopentone is the most commonly used intravenous induction agent in neonates, as propofol is not licensed for induction or maintenance of anaesthesia in the very young. The ED50 for induction agents is the dose that prevents a response in 50% of patients; a concept similar to MAC. The ED50 for thiopentone in neonates is 3.4 mg kg1 compared to 6.3 mg kg1 in infants between 1 and 6 months of age. The reasons for this large age-related difference include an increase in the free fraction of the drug, the increased permeability of the blood-brain barrier, and decreased anaesthetic requirements of the neonate due to immature brain function.

Anaesthetic drugs
The pharmacology of anaesthetic drugs in neonates differs from that in older children because of differences in body size, composition, and immaturity of several organ systems. Water constitutes about 75% by weight of a term neonate, compared to about 57% in the adult, resulting in a proportionately larger extracellular volume and volume of distribution for water-soluble drugs. In contrast, fat constitutes only about 15% of body weight in the neonate, rapidly increasing to about 30% by six months of age, resulting in a smaller volume of distribution for lipophilic drugs. As already described, the immaturity of the renal and hepatic systems further alters drug metabolism and the increased permeability of the blood brain barrier results in an increased sensitivity to some centrally acting drugs.

Opioids
Neonates have increased and variable sensitivity to opioids, particularly with regard to their respiratory depressive effects. Appropriate and continuous monitoring is mandatory for all neonates receiving opioid therapy. Morphine is the most commonly used opioid for peri-operative analgesia in neonates. Morphine is conjugated to the active metabolites morphine-3glucuronide (M3G) and morphine-6-glucuronide (M6G) by glucuronidation; in neonates, the M3G/ M6G ratio is about 5, compared to about 1 in children and adults. Clearances of the renally excreted metabolites are not signicantly affected by postnatal age. Clearance of morphine is about 10 ml min1 kg1 in the term neonate; adult values of morphine clearance (24 ml min1 kg1) are reached by about six months of age. Hence, a single dose of morphine given to a neonate at the onset of surgery will have a prolonged duration of action. Similarly, accumulation of morphine is inevitable during an infusion given in the postoperative period, and repeated assessments of sedation and analgesia requirements, with appropriate adjustments of infusion rate, are required to avoid overdose.

Inhalational anaesthetics
Sevourane and isourane are the most commonly used inhalational anaesthetics in neonatal anaesthetic practice. Sevourane possesses near ideal characteristics as an induction agent, though its cost prohibits its use for prolonged maintenance of anaesthesia. Isourane should not be used to induce anaesthesia, as its pungency causes breath-holding, and laryngospasm; however, it is entirely suitable for maintaining anaesthesia. Uptake and elimination of both these agents is faster in infants compared to adults. Several factors are responsible for this difference, including the high VA/FRC ratio in the neonate; the greater fraction of the neonatal cardiac output being distributed to vessel rich tissues; and lower blood/gas and blood/ tissue partition coefcients.

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General principles of neonatal anaesthesia Fentanyl is a potent opioid that offers relative haemodynamic stability. It is highly lipid soluble and is cleared by hepatic dealkylation and hydroxylation; clearance of fentanyl increases with postconceptional age and birth weight. Clearance of fentanyl in neonates less than one-week old is about 7 ml kg1 min1, compared to 24 ml kg1 min1 at three weeks of age. Neonates with conditions that result in increased intraabdominal pressure, such as after gastroschisis repair, have a further reduction in clearance, probably related to the associated decrease in hepatic blood ow. Remifentanil hydrochloride undergoes rapid hydrolysis by plasma and tissue esterases. In contrast to all other opioids, clearance in neonates (91 ml kg1 min1) is signicantly higher than clearance in adults (47 ml kg1 min1). Volume of distribution is relatively high in infants, but nonetheless, recovery time after a prolonged infusion does not change signicantly with age or development. Bolus doses cause hypotension, and this drug should always be given by continuous infusion; it does not require a loading dose. 307 always be needed. Aspiration problems are extremely rare in neonates, particularly if the stomach is emptied using a nasogastric tube prior to induction. Onset of action of non-depolarizing relaxants such as atracurium or rocuronium is relatively fast in neonates, particularly if a large dose is used (Table 2). Careful pre-operative assessment of the airway is required before such a technique is used. The intermediate acting non-depolarizing muscle relaxants such as atracurium and rocuronium do not normally accumulate after repeated dosing. Atracurium is particularly useful in the neonate as it breaks down spontaneously at body pH and temperature in a process known as Hofmann elimination, which is unaffected by hepatic or renal immaturity. The potency of vecuronium shows more variation with age than other muscle relaxants. The ED50 values are 40% less in infants than children, and the dose should be reduced accordingly (Table 2). The action of nondepolarizing muscle relaxants should be reversed at the end of the procedure if the neonate is to be extubated.

Fluid and electrolyte balance

Muscle relaxants and antagonists


Although both depolarizing and non-depolarizing muscle relaxants can be used to facilitate tracheal intubation in neonates, most experienced paediatric anaesthetists tend to use non-depolarizing relaxants in neonates, even when there is a potential risk of aspiration. The advantages of rapid onset and offset of action of succinylcholine seen in older children are less obvious in neonates. Most neonatal surgery is relatively lengthy in duration, and non-depolarizing relaxants will Normal saline or Ringers lactate solution is equally effective to 5% albumin in the treatment of hypotensive, preterm or term neonates. At present, there is little evidence to suggest that human albumin solution has any particular advantages over other uids as a plasma expander, particularly the newer synthetic colloids, unless plasma albumin concentrations are very low. During major surgical procedures, blood loss should be measured by weighing swabs, or central venous pressure should be monitored. Once blood loss exceeds 10%

Table 2 Drug

Recommended initial dose for commonly used intravenous drugs. Dose 23 mg kg1 2550 mcg kg1 35 mcg kg1 0.5 mg kg1 0.6 mg kg1 70 mcg kg1 50 mcg kg1 20 mcg kg1 Comments Do not repeat dose. Avoid in sick or hypovolaemic neonates Duration of action 46 h. Apnoea monitor and oximeter required postoperatively Duration of action 44 h. Apnoea monitor and oximeter required postoperatively Duration of action 3040 min. Histamine release not a problem in this age group Duration of action 45 min. Monitor effect if further doses required Onset times more rapid in infants compared to children but recovery times are longer Do not give until clinical signs of recovery from neuromuscular block Aim for heart rate 4120 and o160

Thiopentone Morphine Fentanyl Atracurium Rocuronium Vecuronium Neostigmine Atropine

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308 of total blood volume, blood products should be transfused. Dextrose-containing solutions should not be used as plasma expanders. However, there remains a concern that a proportion of neonates may become hypoglycaemic if not given a constant infusion of a dextrose-containing solution. Neonates at particular risk include those o48 h old, preterm, or born to diabetic mothers. A practical compromise that appears to prevent hypoglycaemia, while avoiding hyperglycaemia, is to use lactated Ringers solution containing a low concentration of dextrose (0.92.5%). Maintenance uids should be infused at about 4 ml kg1 h1; electrolytes, glucose and haematocrit should be checked regularly. H. King, P.D. Booker

Further reading
1. Hackman PS. Recognizing and understanding the coldstressed term infant. Neonatal Network 2001;20(8):3541. 2. Beath SV. Hepatic function and physiology in the newborn. Semin Neonatol 2003;8(5):33746. 3. Givan DC. Physiology of breathing and related pathological processes in infants. Semin Pediatr Neurol 2003;10(4):27180. 4. Pierro A. Metabolism and nutritional support in the surgical neonate. J Pediatr Surg 2002;37(6):81122. 5. Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Br J Anaesth 2004;92(2):20817. 6. Meakin GH. Recent advances in myorelaxant therapy. Paediatr Anaesth 2001;11(5):52331.

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