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Inhalation agents in paediatric anaesthesia
Inhalation Agents in Paediatric Anaesthesia
R. H. Taylor and P. M. Crean
Aspects of the pharmacology of established and newer inhaled anaesthetics in children are reviewed. None of the agents discussed meets the characteristics of the 'ideal' inhaled agent in children. It is unfortunate that, although isoflurane and desflurane possess the advantages of low solubility, cardiovascular stability and resistance to metabolism, they both cause irritation of the airway in infants and children. Sevoflurane appears similar in many respects to halothane, providing non-irritant induction, but has the disadvantage of undergoing significant biotransformation and is unstable in fresh soda lime. Further evaluation of the newer agents is required before a final decision on their value in paediatric practice can be made. However, it would appear that halothane is still the most suitable anaesthetic for children, and will remain so for the foreseeable future.
halothane, induction of anaesthesia in children was no more rapid nor as well tolerated, due to its irritant effects on the airway. Minor alterations in chemical structure may produce differing physical properties and clinical effects (Table). The methyl-ethyl ethers, isoflurane and desflurane, have similar structures. The formulation for desflurane is created by the single substitution of a fluoride atom for the chloride atom in isoflurane. Although their physical properties are dissimilar they have much in common, being extremely stable, with similar induction characteristics, and comparable systemic effects. Since desflurane boils at room temperature a modified vaporiser is required for its use. The new Ohmeda Tec 6 vaporiser incorporates features which control precise vapour concentrations with the aid of a thermostatic heater. Recently sevoflurane, a methyl-isopropyl ether, has come under extensive evaluation in infants and children. It possesses different physical and clinical characteristics to other ethers. The heavier molecular structure is less 'balanced' around the ether bond and it is significantly less stable than other ether anaesthetics in vivo and in vitro. It's non-pungent odour and low solubility suggests a rapid induction and recovery from anaesthesia in
Inhaled anaesthetics continue to form the basis of the vast majority of anaesthetics given to infants and children. This is largely due to the fact that inhalational induction of anaesthesia may be preferred as prior venous access is not essential. Furthermore, they provide predictable levels of anaesthesia, with breath to breath control, and with little likelihood of awareness. Knowledge of age-related differences in the pharmacology of inhaled anaesthetics is essential for their safe and effective use in children. Halothane, an alkane, was first introduced into clinical practice in 1956 and was soon recognised as being a major improvement over existing agents. It provided rapid and safe inhalation induction of anaesthesia, due to its relatively low solubility and lack of pungency. However, drawbacks such as myocardial depression, rhythm disturbances, and hepatotoxicity became evident in due course. More than two decades later isoflurane, a methyl-ethyl ether, became established as an alternative to halothane. However, despite a lower solubility than R. H. Taylor MB, FFARCSI, P. M. Crean MB, FFARCSI, The Royal Belfast Hospital for Sick Children, Falls Road, Belfast BTI2 6BE, Northern Ireland (Correspondence to PMC) Current Anaesthesia and Critical Care
© 1994LongmanGroupLtd
(1994)5, 197-201 1 97
198
CURRENTANAESTHESIAAND CRITICAL CARE Table I--The chemical structures and properties of four potent inhaled anaesthetics.Note the differences in MAC between adults and infants and the age-related decreases in systolic arterial pressure (SAP) at l MAC compared to awake values.6,1°.m6Differencesin heart rate and induction characteristics are agent specific. Halothane Chemical structure Boiling point (°C) Metabolised (%) Blood/gas Solubility: adults neonates MAC adults neonates MAC depression by N20 (%)* adults children SAP reduction (%) children neonates preterm Heart Rate Anaesthetic Induction
CF3-CHCIBr 50.2 15-20
Isoflurane
Desflurane
Sevoflurane
CHF2-O-CHCI-CF 3 48.5 0.2
CHFz-O-CHF-CF3 23.5 0.02
CH2F-O-CH(CF3)CF3 58.6 3.3
2.4 2.1
1.4 1.2
0.42 -
0.66 0.66
0.75 0.87
1.2 1.6
7.0 9.2
2.05 3'.3
53 60
60 40
53 26
24
13 23 25 -1. Smooth
16 30 1" Irritant
22 34 or -l. Irritant
0 34 - or 1" Smooth (+ excitation)
*Depression of MAC with the addition of approximately 60% nitrous oxide.
children. However, induction time is no more rapid than with halothane and excitation during induction and recovery is not uncommon. Also, there is concern about its metabolism and absorption in soda-lime. Although likely to be a useful agent in paediatric anaesthesia, sevoflurane requires further evaluation.
Pharmacokinetics Uptake and distribution The rate of uptake and distribution of inhaled anaesthetic agents is different in children as compared to adults. Salanitre and Rackow were the first to demonstrate that the alveolar partial pressure of halothane rises more rapidly to approximate the inspired partial pressure in children compared to adults. 1 This also applies to other inhaled anaesthetics, 2 being attributed to factors determining the rate of delivery of the inhaled anaesthetic to the lung (inspired concentration, alveolar ventilation, functional residual capacity), and to those affecting the rate of uptake from the lung (cardiac output, solubility, alveolar to venous partial pressure gradient). The effect of inspired concentration is only relevant to those agents used in high concentration, such as nitrous oxide. The rate of wash-in o f an anaesthetic into the alveoli is dependant on the relationship between alveolar ventilation and functional residual capacity. The larger the ratio of these two, the faster is the rate of rise. As this is 5:1 in the neonate compared to only 1.5:1 in the adult, a more rapid uptake is to be expected. The difference in this ratio is the result of relatively greater alveolar ventilation in the neonate, reflecting higher metabolic demands. Functional residual capacity remains constant with increasing age from neonates to young adults on a ml/kg basis. In adults, increases in cardiac output slow the rate of rise of alveolar to inspired anaesthetic partial pressure. In contrast, the increased cardiac output in neonates
accelerates this rate of rise, because blood flow is preferentially distributed to the vessel rich groups (VRG), which comprises 18% of the body weight as compared to only 6% in the adult. Thus, in neonates, the partial pressure of inhaled anaesthetics in the V R G equilibrates more rapidly with the alveolar partial pressure, resulting in faster equilibration between the alveolar and inspired anaesthetic partial pressures. The solubility o f an anaesthetic is an index of the relative capacity per unit volume of two solvents, such as blood and gas, for that agent. The less soluble the agent is in blood or tissue, the greater is the amount that will remain at alveolar level, leading to more rapid equilibration between alveolar and inspired partial pressures. This occurs with halothane and isoflurane in preterm and term infants, the solubility of these agents in blood being 18% less than adult values? Also, with agents of low solubility, the tissues will take up less from blood in achieving partial pressure equilibrium. Therefore, the partial pressure in venous blood increases at a faster rate, thereby decreasing the alveolar to venous partial pressure gradient. As less anaesthetic is removed from the lungs, more rapid equilibration of alveolar to inspired anaesthetic concentrations results. In the first 20 minutes of exposure to an inhaled anaesthetic, the pharmacokinetics are mainly dependant on the characteristics of the VRG. However, subsequently the muscle group becomes more important. The solubilities of halothane and isoflurane in the V R G in neonates are approximately half adult values. 4 This m a y be attributed to neonatal tissue having a greater water content and a lower protein and lipid content. Solubility in skeletal muscle varies logarithmically with age, a lower value in the neonate leading to a faster rise in alveolar to inspired anaesthetic partial pressure as compared to the adult. This finding is due to an increase in protein concentration and fat content in muscle with age. It has been found that, in children, the rate of wash-
INHALATIONAGENTSIN PAEDIATRICANAESTHESIA 199 in of more soluble anaesthetics is age-related. 2 Under conditions of controlled alveolar ventilation the rate of wash-in decreases as children become older. However, this is not the case for the less soluble agent isoflurane, whose uptake was uniformly rapid in all children. Desflurane and sevoflurane, agents with lower solubility, may behave in a similar manner.
Metabolism All inhaled anaesthetics undergo biotransformation to a certain degree (halothane 15-20%, sevoflurane 3.3%, enflurane 2%, isoflurane 0.2% and desflurane 0.02%). This effect is probably less marked in infants and children than in adults. The reductive pathways in the liver are poorly developed in infants and children, with halothane hepatitis being rare in this age group. However, hepatologists have reported several cases of this complication, one with a fatal outcome, and they suggest that repeated exposure to halothane should be avoided in children? Nevertheless, millions of repeat halothane anaesthetics have been given to children without illeffects and the use of less appropriate agents in children could replace the rare case of halothane hepatitis by a higher incidence of other complications. Sevoflurane undergoes biotransformation with the release of inorganic fluoride ion. The mean peak plasma fluoride concentration in children of less than 20 gmol/L is less than the value of 29 gmol/L in adults, and substantially lower than the generally accepted serum nephrotoxic threshold of 50 gmol]L. 6 The information which is available regarding the possible nephrotoxic hazard of sevoflurane is still limited and it is clear that further study is required. Sevoflurane differs from halothane, isoflurane and desflurane in being unstable in fresh soda lime (15% water), even at increased temperature. Desflurane is the least degraded of all inhaled agents being one-tenth that of isoflurane.
Recovery Recovery time to eye opening is faster with the less soluble anaesthetics. In comparative studies, emergence from either desflurane 7 or sevoflurane 8 anaesthesia was significantly more rapid than with halothane. However, this improvement in recovery did not reduce discharge times in children undergoing day-care surgery.
Pharmacodynamics The potency of an inhaled anaesthetic is determined by its minimum alveolar concentration (MAC). This is defined as the alveolar anaesthetic concentration at which 50% of patients do not move in response to a skin incision. MAC is lower in preterm infants than that in term infants and increases with gestational age 9 (Fig.). MAC generally increases to a maximum level by 6 months of age and, thereafter, decreases with increasing age. 6,1°-12The potency of sevoflurane is somewhat un-
MAC (% ISOFLURANE)
/--,
20 t
1.8
1.6-
/ •
/
1.4 •
32 - 37 wks
<32
wks
geslation
gestalion
\
1.2
1.0
I
'
0.5
' ')1
I
'
' '~I
*
'
I
1.0 5 10 50 POST CONCEPTUAL AGE (YEARS)
'
'
''1
100
Fig.--The effect of increasing age on MAC of isoflurane. MAC increases with gestational age to a peak at 6 months of age and thereafter decreases with increasing age. (Reproduced by kind permission of J. B. Lippincott Company from LeDez and Lermang.)
usual in that there does not appear to be an age related difference in MAC during early infancy. After 6 months of age an abrupt step down in MAC has been observed with sevoflurane, after which time it remains constant during childhood. 6 This age related difference in MAC should be recognised since differing alveolar anaesthetic concentrations will give rise to comparable levels of anaesthesia. In other words the same alveolar concentration will produce different levels of anaesthesia in different age groups of children. The MAC of nitrous oxide is not related to age. In adults, 60% nitrous oxide reduces the MAC of most inhaled anaesthetics by about 60%. However, this additive effect is different in infants and young children, with the MAC of halothane being reduced by approximately 60%, 13 isoflurane by 40%, ~4 desflurane by 26%, 15 and sevoflurane by 24%. 6 It would appear that the additive effect of nitrous oxide to the potency of inhaled anaesthetics in children is most marked with the more soluble agents, a difference which has yet to be explained.
Cardiovascular effects Reductions in arterial blood pressure occur with all the inhaled agents and are dose dependent. The incidence of hypotension in neonates is comparable to infants with equipotent doses (1 MAC) of halothane or desflurane. ~0,~2 However, several neonates who received desflurane required crystalloid 5 ml/kg to maintain systolic arterial pressure (SAP)? 2 Sevoflurane produces hypotension more frequently in neonates than older children and crystalloid infusion is often required to maintain blood pressure. 6 In premature infants halothane and isoflurane produce a similar decrease in SAP to fentanyl. However, decreases in SAP occur less frequently using ketamine. 16 The heart rate decreases in infants and young children
200
CURRENT ANAESTHESIA AND CRITICAL CARE
given either halothane or desflurane, 12but is unchanged with sevoflurane, and may even increase in older children. 6 Heart rate increases in children given isoflurane. 9,16 This suggests that the baroreflex is maintained with isoflurane and sevoflurane to some extent, but not with halothane or desflurane. Isoflurane maintains cardiac output by both heart rate and stroke volume, as measured by aortic peak flow velocity, unlike halothane. 17 In children, reductions in peripheral vascular resistance are partly responsible for the decreases in arterial pressure, when concentrations of less than 1.5 MAC halothane and isoflurane are used. Peripheral blood flow studies suggest that increasing concentrations of these agents cause progressive increases in forearm blood flow and reductions in vascular resistance? 8,19By contrast, isoflurane causes greater peripheral vasodilatation than halothane in adults. Isoflurane significantly reduces hand vascular resistance in children, increasing hand blood flow in a dose related fashion. However, halothane causes vasodilatation which is almost maximal at 0.5 MAC with little further change thereafter. Changes in hand blood flow can be regarded as in indication of alterations of peripheral sympathetic tone. The effects of halothane on hand blood flow are suggestive of a sharp and possibly maximal reduction in hand sympathetic tone at 0.5 MAC. Isoflurane causes a progressive dose related reduction in vascular tone similar to its effects on the forearm vasculature. Evaluation of the peripheral cardiovascular haemodynamics of the newer agents are required in children. There is a 2-5% incidence of A-V nodal rhythm during induction with either desflurane or sevoflurane. 6,~2 In pigs the threshold dose of adrenaline to produce ventricular arrythmias with desflurane or isoflurane is about four times greater than that found with halothane. 2° The threshold dose of adrenaline for arrythmias during anaesthesia in children has not been studied. However, in the presence of halothane ventricular arrythmias with adrenaline infiltration are less likely to occur in children compared to adults. 2~
Respiratory effects To many halothane is still the preferred inhaled anaesthetic with which other agents are compared. Despite the lower blood/gas partition coefficients of isoflurane and desflurane, which should theoretically accelerate induction, these agents may in fact prolong induction in comparison to halothane. This is due to their irritant effects on the airway which can cause coughing, breath-holding, salivation, and laryngeal spasm and may result in arterial oxygen desaturation. 22'23 Various attempts to attenuate the airway effects of isoflurane have been reported, and include atropine premedication, rectal thiopentone premedication, and overpressure. Although desflurane is not recommended for inhalational induction of anaesthesia in children such measures have not been reported and may make it more acceptable. Sevoflurane, unlike isoflurane and desflurane, appears to produce a smooth
inductiofi of anaesthesia. 6,8Agitation, or excitation, has been noted and may be confused with transient seizurelike activity. 8,24 The time to loss of eyelash reflex with sevoflurane in nitrous oxide is no faster than halothane. 8 All inhaled anaesthetics depress alveolar minute ventilation, producing an increase in arterial carbon dioxide tension, despite increases in respiratory rate. Halothane and isoflurane cause comparable decreases in tidal volume and ventilatory response to carbon dioxideY Sevoflurane is a more potent respiratory depressant than halothane at higher MAC values (> 1.5 MAC). 26 Inhaled anaesthetics at alveolar concentrations of greater than 2 MAC abolish airway reflexes and provide suitable conditions for tracheal intubation, although such levels of anaesthesia will cause significant cardiovascular depression. Recovery from inhaled anaesthetics is dependent on the drug used. Airway complications and arterial oxygen desaturation are more common when children are extubated awake following isoflurane anaesthesia compared to halothane? 7 However, there is no difference between the agents when extubation occurs in a deep plane of anaesthesia. Airway compfications and arterial oxygen desaturation have not been reported during recovery from desflurane anaesthesia. Sevoflurane has also been noted to produce agitation during recovery.26
Other effects Inhaled anaesthetics provide dose-related muscle relaxation. Halothane and isoflurane both increase the potency of non-depolarising neuromuscular blocking agents to the same degree in children, but only isoflurane prolongs the duration of block. 28 Excellent intubating conditions using 2 MAC desflurane have been described, suggesting that it also provides good muscle relaxation. 29 All the inhaled anaesthetics decrease cerebral vascular resistance, CMRO 2, and increase cerebral blood flow in a dose dependent manner. Studies using transcranial doppler in children indicate that, with hypocapnia established, neither 1 MAC halothane nor isoflurane affects the CO2 reactivity of the cerebral circulation, suggesting that autoregulation is maintained? ° The effects of desflurane on cerebral blood flow and intracranial pressure have not been studied in children. In adult patients desflurane and sevoflurane (< 1 MAC) appear to be similar to isoflurane. 31Although sevoflurane produces transient muscle rigidity during induction in children and a 'peculiar EEG pattern', it can suppress lignocaine induced seizures? 1None of the inhaled anaesthetics predispose to convulsive activity, with the exception of enflurane..
References 1. Salanitre E, Rackow H. The pulmonary exchange of nitrous oxide and halothane in infants and children. Anesthesiology 1969; 30: 388-394. 2. Gallagher T M, Black G W. Uptake of volatile anaesthetics in children. Anaesthesia 1985; 40: 1073-1077.
INHALATION AGENTS IN PAED1ATRIC ANAESTHESIA 3. Lerman J, Gregory G A, Willis M M, Eger E I II. Age and solubility of volatile anesthetics in blood. Anesthesiology 1984; 61: 139-143. 4. Lerman J, Schmitt-Banter B I, Gregory G A, Willis M M, Eger E I II. Effect of age on the solubility of volatile anesthetics in human tissues. Anesthesiology 1986; 65: 307-311. 5. Kenna J G, Neuberger J, Mieli-Vergani G, Mowat A P, Williams R. Halothane hepatitis in children. BMJ 1987; 294:120%1211. 6. Lerman J, Sikich N, Kleinman S, Yentis S. The pharmacology of sevoflurane in infants and children. Anesthesiology 1994; 80: 814-824. 7. Davis P J, Cohen I T, McGowan F X, Latta K. Recovery characteristics of desflurane versus halothane for maintenance of anesthesia in pediatric ambulatory patients. Anesthesiology 1994; 80: 298-302. 8. Naito Y, Tamai S, Shingu K, Fujimori R, Mori K. Comparison between sevoflurane and halothane for paediatric ambulatory anaesthesia. Br J Anaesth 1991; 67(4): 387-389. 9. LeDez K M, Lerman J. The minimum alveolar concentration (MAC) of isoflurane in preterm neonates. Anesthesiology 1987; 67: 301-307. 10. Lerman J, Robinson S, Willis M M, Gregory G A. Anesthetic requirements for halothane in young children 0-1 month and 1-6 months of age. Anesthesiology 1983; 59: 421-424. 11. Cameron C B, Robinson S, Gregory G A. The minimum anesthetic concentration of isoflurane in children. Anesthesiology 1984; 63: 418-420. 12. Taylor R H, Lerman J. Minimum Alveolar Concentration of desflurane and hemodynamic responses in infants and children. Anesthesiology 1991; 75: 975-979. 13. Murray D J, Mehta M P, Forbes R B, Dull D L. Additive contribution of nitrous oxide to halothane MAC in infants and children. Anesth Analg 1990; 71: 120-124. 14. Murray D J, Mehta M P, Forbes R B. The additive contribution of nitrous oxide to isoflurane MAC in infants and children. Anesthesiology 1991; 75: 186-190. 15. Fisher D M, Zwass M S. MAC of desflurane in 60% nitrous oxide in infants and children. Anesthesiology 1992; 76: 354-356. 16. Freisen R H, Henry D B. Cardiovascular changes in preterm neonates receiving isoflurane, halothane, fentanyl, and ketamine. Anesthesiology 1986; 64: 238-242. 17. Gallagher T M, Shields M D, Black G W. Isoflurane does not reduce aortic peak flow velocity in children. Br J Anaesth 1986; 58: 1116-1121. 18. Laird C R D, Mulholland D, Crean P M, Black G W. The effects of
201
halothane and isoflurane on hand blood flow in children as determined by venous occlusion plethysmography. Paediatric Anaesthesia 1993; 3: 7%82. 19. Mulholland D, Laird C R D, Crean P M, Black G W. The effects of halothane and isoflurane on forearm blood flow in children (as determined by venous occlusion plethysmography). Paediatric Anaesthesia 1994; 4: 83-86. 20. Weiskopf R B, Eger E IlI, Holmes M A e t al. Epinephrineinduced premature ventricular contractions and changes in arterial blood pressure and heart rate during 1-653, isoflurane, and halothane anesthesia in swine. Anesthesiology 1989; 70(2): 293-298. 21. Karl H W, Swedlow D B, Lee K W, Downes J J. Epinephrinehalothane interactions in children. Anesthesiology 1983; 58: 142-145. 22. Zwass M S, Fisher D M, Welborn L G e t al. Induction and maintenance characteristics of anesthesia with desflurane and nitrous oxide in infants and children. Anesthesiology 1992; 76: 373-378. 23. Sampaio M M, Crean P M, Keilty S R, Black G W. Changes in oxygen saturation during inhalation induction of anaesthesia in children. Br J Anaesth 1989; 62: 199-201. 24. Moto R, Miyasaka K, Takata M, Kondo Y, Asahara S. Initial experience of complete switchover to sevoflurane in 1550 children. Paediatric Anaesthesia 1993; 3: 229-233. 25. Hatch D, Fletcher M. Anaesthesia and the ventilatory system in infants and young children. Br J Anaesth 1992; 68: 398-410. 26. Yamakage M, Tamiya K, Horikawa D, Sato K, Namiki A. Effects of halothane and sevoflurane on the paediatric respiratory pattern. Paediatric Anaesthesia 1994; 4: 53-56. 27. Pounder D R, Blackstock D, Steward D J. Tracheal extubation in children: Halothane versus isoflurane, anesthetized versus awake. Anesthesiology 1991; 74: 653-655. 28. Pittet J F, Melis A, Rouge J C, Morel D R, Gemperle G, Tassonyi E. Effect of volatile anaesthetics on vecuronium-induced neuromuscular blockade in children. Anesth Analg 1990; 70: 248-252. 29. Taylor R H, Lerman J. Induction, maintenance and recovery characteristics of desflurane in neonates, infants and children. Can J Anaesth 1992; 39: 6-13. 30. Leon J E, Bissonnette B. Cerebrovascular responses to carbon dioxide in children anaesthetized with halothane and isoflurane. Can J Anaesth 1991; 38: 817-825. 31. Eger E III. New Inhaled anaesthetics. Anesthesiology 1994; 80: 906-922.
R. H. Taylor and P. M. Crean
Aspects of the pharmacology of established and newer inhaled anaesthetics in children are reviewed. None of the agents discussed meets the characteristics of the 'ideal' inhaled agent in children. It is unfortunate that, although isoflurane and desflurane possess the advantages of low solubility, cardiovascular stability and resistance to metabolism, they both cause irritation of the airway in infants and children. Sevoflurane appears similar in many respects to halothane, providing non-irritant induction, but has the disadvantage of undergoing significant biotransformation and is unstable in fresh soda lime. Further evaluation of the newer agents is required before a final decision on their value in paediatric practice can be made. However, it would appear that halothane is still the most suitable anaesthetic for children, and will remain so for the foreseeable future.
halothane, induction of anaesthesia in children was no more rapid nor as well tolerated, due to its irritant effects on the airway. Minor alterations in chemical structure may produce differing physical properties and clinical effects (Table). The methyl-ethyl ethers, isoflurane and desflurane, have similar structures. The formulation for desflurane is created by the single substitution of a fluoride atom for the chloride atom in isoflurane. Although their physical properties are dissimilar they have much in common, being extremely stable, with similar induction characteristics, and comparable systemic effects. Since desflurane boils at room temperature a modified vaporiser is required for its use. The new Ohmeda Tec 6 vaporiser incorporates features which control precise vapour concentrations with the aid of a thermostatic heater. Recently sevoflurane, a methyl-isopropyl ether, has come under extensive evaluation in infants and children. It possesses different physical and clinical characteristics to other ethers. The heavier molecular structure is less 'balanced' around the ether bond and it is significantly less stable than other ether anaesthetics in vivo and in vitro. It's non-pungent odour and low solubility suggests a rapid induction and recovery from anaesthesia in
Inhaled anaesthetics continue to form the basis of the vast majority of anaesthetics given to infants and children. This is largely due to the fact that inhalational induction of anaesthesia may be preferred as prior venous access is not essential. Furthermore, they provide predictable levels of anaesthesia, with breath to breath control, and with little likelihood of awareness. Knowledge of age-related differences in the pharmacology of inhaled anaesthetics is essential for their safe and effective use in children. Halothane, an alkane, was first introduced into clinical practice in 1956 and was soon recognised as being a major improvement over existing agents. It provided rapid and safe inhalation induction of anaesthesia, due to its relatively low solubility and lack of pungency. However, drawbacks such as myocardial depression, rhythm disturbances, and hepatotoxicity became evident in due course. More than two decades later isoflurane, a methyl-ethyl ether, became established as an alternative to halothane. However, despite a lower solubility than R. H. Taylor MB, FFARCSI, P. M. Crean MB, FFARCSI, The Royal Belfast Hospital for Sick Children, Falls Road, Belfast BTI2 6BE, Northern Ireland (Correspondence to PMC) Current Anaesthesia and Critical Care
© 1994LongmanGroupLtd
(1994)5, 197-201 1 97
198
CURRENTANAESTHESIAAND CRITICAL CARE Table I--The chemical structures and properties of four potent inhaled anaesthetics.Note the differences in MAC between adults and infants and the age-related decreases in systolic arterial pressure (SAP) at l MAC compared to awake values.6,1°.m6Differencesin heart rate and induction characteristics are agent specific. Halothane Chemical structure Boiling point (°C) Metabolised (%) Blood/gas Solubility: adults neonates MAC adults neonates MAC depression by N20 (%)* adults children SAP reduction (%) children neonates preterm Heart Rate Anaesthetic Induction
CF3-CHCIBr 50.2 15-20
Isoflurane
Desflurane
Sevoflurane
CHF2-O-CHCI-CF 3 48.5 0.2
CHFz-O-CHF-CF3 23.5 0.02
CH2F-O-CH(CF3)CF3 58.6 3.3
2.4 2.1
1.4 1.2
0.42 -
0.66 0.66
0.75 0.87
1.2 1.6
7.0 9.2
2.05 3'.3
53 60
60 40
53 26
24
13 23 25 -1. Smooth
16 30 1" Irritant
22 34 or -l. Irritant
0 34 - or 1" Smooth (+ excitation)
*Depression of MAC with the addition of approximately 60% nitrous oxide.
children. However, induction time is no more rapid than with halothane and excitation during induction and recovery is not uncommon. Also, there is concern about its metabolism and absorption in soda-lime. Although likely to be a useful agent in paediatric anaesthesia, sevoflurane requires further evaluation.
Pharmacokinetics Uptake and distribution The rate of uptake and distribution of inhaled anaesthetic agents is different in children as compared to adults. Salanitre and Rackow were the first to demonstrate that the alveolar partial pressure of halothane rises more rapidly to approximate the inspired partial pressure in children compared to adults. 1 This also applies to other inhaled anaesthetics, 2 being attributed to factors determining the rate of delivery of the inhaled anaesthetic to the lung (inspired concentration, alveolar ventilation, functional residual capacity), and to those affecting the rate of uptake from the lung (cardiac output, solubility, alveolar to venous partial pressure gradient). The effect of inspired concentration is only relevant to those agents used in high concentration, such as nitrous oxide. The rate of wash-in o f an anaesthetic into the alveoli is dependant on the relationship between alveolar ventilation and functional residual capacity. The larger the ratio of these two, the faster is the rate of rise. As this is 5:1 in the neonate compared to only 1.5:1 in the adult, a more rapid uptake is to be expected. The difference in this ratio is the result of relatively greater alveolar ventilation in the neonate, reflecting higher metabolic demands. Functional residual capacity remains constant with increasing age from neonates to young adults on a ml/kg basis. In adults, increases in cardiac output slow the rate of rise of alveolar to inspired anaesthetic partial pressure. In contrast, the increased cardiac output in neonates
accelerates this rate of rise, because blood flow is preferentially distributed to the vessel rich groups (VRG), which comprises 18% of the body weight as compared to only 6% in the adult. Thus, in neonates, the partial pressure of inhaled anaesthetics in the V R G equilibrates more rapidly with the alveolar partial pressure, resulting in faster equilibration between the alveolar and inspired anaesthetic partial pressures. The solubility o f an anaesthetic is an index of the relative capacity per unit volume of two solvents, such as blood and gas, for that agent. The less soluble the agent is in blood or tissue, the greater is the amount that will remain at alveolar level, leading to more rapid equilibration between alveolar and inspired partial pressures. This occurs with halothane and isoflurane in preterm and term infants, the solubility of these agents in blood being 18% less than adult values? Also, with agents of low solubility, the tissues will take up less from blood in achieving partial pressure equilibrium. Therefore, the partial pressure in venous blood increases at a faster rate, thereby decreasing the alveolar to venous partial pressure gradient. As less anaesthetic is removed from the lungs, more rapid equilibration of alveolar to inspired anaesthetic concentrations results. In the first 20 minutes of exposure to an inhaled anaesthetic, the pharmacokinetics are mainly dependant on the characteristics of the VRG. However, subsequently the muscle group becomes more important. The solubilities of halothane and isoflurane in the V R G in neonates are approximately half adult values. 4 This m a y be attributed to neonatal tissue having a greater water content and a lower protein and lipid content. Solubility in skeletal muscle varies logarithmically with age, a lower value in the neonate leading to a faster rise in alveolar to inspired anaesthetic partial pressure as compared to the adult. This finding is due to an increase in protein concentration and fat content in muscle with age. It has been found that, in children, the rate of wash-
INHALATIONAGENTSIN PAEDIATRICANAESTHESIA 199 in of more soluble anaesthetics is age-related. 2 Under conditions of controlled alveolar ventilation the rate of wash-in decreases as children become older. However, this is not the case for the less soluble agent isoflurane, whose uptake was uniformly rapid in all children. Desflurane and sevoflurane, agents with lower solubility, may behave in a similar manner.
Metabolism All inhaled anaesthetics undergo biotransformation to a certain degree (halothane 15-20%, sevoflurane 3.3%, enflurane 2%, isoflurane 0.2% and desflurane 0.02%). This effect is probably less marked in infants and children than in adults. The reductive pathways in the liver are poorly developed in infants and children, with halothane hepatitis being rare in this age group. However, hepatologists have reported several cases of this complication, one with a fatal outcome, and they suggest that repeated exposure to halothane should be avoided in children? Nevertheless, millions of repeat halothane anaesthetics have been given to children without illeffects and the use of less appropriate agents in children could replace the rare case of halothane hepatitis by a higher incidence of other complications. Sevoflurane undergoes biotransformation with the release of inorganic fluoride ion. The mean peak plasma fluoride concentration in children of less than 20 gmol/L is less than the value of 29 gmol/L in adults, and substantially lower than the generally accepted serum nephrotoxic threshold of 50 gmol]L. 6 The information which is available regarding the possible nephrotoxic hazard of sevoflurane is still limited and it is clear that further study is required. Sevoflurane differs from halothane, isoflurane and desflurane in being unstable in fresh soda lime (15% water), even at increased temperature. Desflurane is the least degraded of all inhaled agents being one-tenth that of isoflurane.
Recovery Recovery time to eye opening is faster with the less soluble anaesthetics. In comparative studies, emergence from either desflurane 7 or sevoflurane 8 anaesthesia was significantly more rapid than with halothane. However, this improvement in recovery did not reduce discharge times in children undergoing day-care surgery.
Pharmacodynamics The potency of an inhaled anaesthetic is determined by its minimum alveolar concentration (MAC). This is defined as the alveolar anaesthetic concentration at which 50% of patients do not move in response to a skin incision. MAC is lower in preterm infants than that in term infants and increases with gestational age 9 (Fig.). MAC generally increases to a maximum level by 6 months of age and, thereafter, decreases with increasing age. 6,1°-12The potency of sevoflurane is somewhat un-
MAC (% ISOFLURANE)
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1.0 5 10 50 POST CONCEPTUAL AGE (YEARS)
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Fig.--The effect of increasing age on MAC of isoflurane. MAC increases with gestational age to a peak at 6 months of age and thereafter decreases with increasing age. (Reproduced by kind permission of J. B. Lippincott Company from LeDez and Lermang.)
usual in that there does not appear to be an age related difference in MAC during early infancy. After 6 months of age an abrupt step down in MAC has been observed with sevoflurane, after which time it remains constant during childhood. 6 This age related difference in MAC should be recognised since differing alveolar anaesthetic concentrations will give rise to comparable levels of anaesthesia. In other words the same alveolar concentration will produce different levels of anaesthesia in different age groups of children. The MAC of nitrous oxide is not related to age. In adults, 60% nitrous oxide reduces the MAC of most inhaled anaesthetics by about 60%. However, this additive effect is different in infants and young children, with the MAC of halothane being reduced by approximately 60%, 13 isoflurane by 40%, ~4 desflurane by 26%, 15 and sevoflurane by 24%. 6 It would appear that the additive effect of nitrous oxide to the potency of inhaled anaesthetics in children is most marked with the more soluble agents, a difference which has yet to be explained.
Cardiovascular effects Reductions in arterial blood pressure occur with all the inhaled agents and are dose dependent. The incidence of hypotension in neonates is comparable to infants with equipotent doses (1 MAC) of halothane or desflurane. ~0,~2 However, several neonates who received desflurane required crystalloid 5 ml/kg to maintain systolic arterial pressure (SAP)? 2 Sevoflurane produces hypotension more frequently in neonates than older children and crystalloid infusion is often required to maintain blood pressure. 6 In premature infants halothane and isoflurane produce a similar decrease in SAP to fentanyl. However, decreases in SAP occur less frequently using ketamine. 16 The heart rate decreases in infants and young children
200
CURRENT ANAESTHESIA AND CRITICAL CARE
given either halothane or desflurane, 12but is unchanged with sevoflurane, and may even increase in older children. 6 Heart rate increases in children given isoflurane. 9,16 This suggests that the baroreflex is maintained with isoflurane and sevoflurane to some extent, but not with halothane or desflurane. Isoflurane maintains cardiac output by both heart rate and stroke volume, as measured by aortic peak flow velocity, unlike halothane. 17 In children, reductions in peripheral vascular resistance are partly responsible for the decreases in arterial pressure, when concentrations of less than 1.5 MAC halothane and isoflurane are used. Peripheral blood flow studies suggest that increasing concentrations of these agents cause progressive increases in forearm blood flow and reductions in vascular resistance? 8,19By contrast, isoflurane causes greater peripheral vasodilatation than halothane in adults. Isoflurane significantly reduces hand vascular resistance in children, increasing hand blood flow in a dose related fashion. However, halothane causes vasodilatation which is almost maximal at 0.5 MAC with little further change thereafter. Changes in hand blood flow can be regarded as in indication of alterations of peripheral sympathetic tone. The effects of halothane on hand blood flow are suggestive of a sharp and possibly maximal reduction in hand sympathetic tone at 0.5 MAC. Isoflurane causes a progressive dose related reduction in vascular tone similar to its effects on the forearm vasculature. Evaluation of the peripheral cardiovascular haemodynamics of the newer agents are required in children. There is a 2-5% incidence of A-V nodal rhythm during induction with either desflurane or sevoflurane. 6,~2 In pigs the threshold dose of adrenaline to produce ventricular arrythmias with desflurane or isoflurane is about four times greater than that found with halothane. 2° The threshold dose of adrenaline for arrythmias during anaesthesia in children has not been studied. However, in the presence of halothane ventricular arrythmias with adrenaline infiltration are less likely to occur in children compared to adults. 2~
Respiratory effects To many halothane is still the preferred inhaled anaesthetic with which other agents are compared. Despite the lower blood/gas partition coefficients of isoflurane and desflurane, which should theoretically accelerate induction, these agents may in fact prolong induction in comparison to halothane. This is due to their irritant effects on the airway which can cause coughing, breath-holding, salivation, and laryngeal spasm and may result in arterial oxygen desaturation. 22'23 Various attempts to attenuate the airway effects of isoflurane have been reported, and include atropine premedication, rectal thiopentone premedication, and overpressure. Although desflurane is not recommended for inhalational induction of anaesthesia in children such measures have not been reported and may make it more acceptable. Sevoflurane, unlike isoflurane and desflurane, appears to produce a smooth
inductiofi of anaesthesia. 6,8Agitation, or excitation, has been noted and may be confused with transient seizurelike activity. 8,24 The time to loss of eyelash reflex with sevoflurane in nitrous oxide is no faster than halothane. 8 All inhaled anaesthetics depress alveolar minute ventilation, producing an increase in arterial carbon dioxide tension, despite increases in respiratory rate. Halothane and isoflurane cause comparable decreases in tidal volume and ventilatory response to carbon dioxideY Sevoflurane is a more potent respiratory depressant than halothane at higher MAC values (> 1.5 MAC). 26 Inhaled anaesthetics at alveolar concentrations of greater than 2 MAC abolish airway reflexes and provide suitable conditions for tracheal intubation, although such levels of anaesthesia will cause significant cardiovascular depression. Recovery from inhaled anaesthetics is dependent on the drug used. Airway complications and arterial oxygen desaturation are more common when children are extubated awake following isoflurane anaesthesia compared to halothane? 7 However, there is no difference between the agents when extubation occurs in a deep plane of anaesthesia. Airway compfications and arterial oxygen desaturation have not been reported during recovery from desflurane anaesthesia. Sevoflurane has also been noted to produce agitation during recovery.26
Other effects Inhaled anaesthetics provide dose-related muscle relaxation. Halothane and isoflurane both increase the potency of non-depolarising neuromuscular blocking agents to the same degree in children, but only isoflurane prolongs the duration of block. 28 Excellent intubating conditions using 2 MAC desflurane have been described, suggesting that it also provides good muscle relaxation. 29 All the inhaled anaesthetics decrease cerebral vascular resistance, CMRO 2, and increase cerebral blood flow in a dose dependent manner. Studies using transcranial doppler in children indicate that, with hypocapnia established, neither 1 MAC halothane nor isoflurane affects the CO2 reactivity of the cerebral circulation, suggesting that autoregulation is maintained? ° The effects of desflurane on cerebral blood flow and intracranial pressure have not been studied in children. In adult patients desflurane and sevoflurane (< 1 MAC) appear to be similar to isoflurane. 31Although sevoflurane produces transient muscle rigidity during induction in children and a 'peculiar EEG pattern', it can suppress lignocaine induced seizures? 1None of the inhaled anaesthetics predispose to convulsive activity, with the exception of enflurane..
References 1. Salanitre E, Rackow H. The pulmonary exchange of nitrous oxide and halothane in infants and children. Anesthesiology 1969; 30: 388-394. 2. Gallagher T M, Black G W. Uptake of volatile anaesthetics in children. Anaesthesia 1985; 40: 1073-1077.
INHALATION AGENTS IN PAED1ATRIC ANAESTHESIA 3. Lerman J, Gregory G A, Willis M M, Eger E I II. Age and solubility of volatile anesthetics in blood. Anesthesiology 1984; 61: 139-143. 4. Lerman J, Schmitt-Banter B I, Gregory G A, Willis M M, Eger E I II. Effect of age on the solubility of volatile anesthetics in human tissues. Anesthesiology 1986; 65: 307-311. 5. Kenna J G, Neuberger J, Mieli-Vergani G, Mowat A P, Williams R. Halothane hepatitis in children. BMJ 1987; 294:120%1211. 6. Lerman J, Sikich N, Kleinman S, Yentis S. The pharmacology of sevoflurane in infants and children. Anesthesiology 1994; 80: 814-824. 7. Davis P J, Cohen I T, McGowan F X, Latta K. Recovery characteristics of desflurane versus halothane for maintenance of anesthesia in pediatric ambulatory patients. Anesthesiology 1994; 80: 298-302. 8. Naito Y, Tamai S, Shingu K, Fujimori R, Mori K. Comparison between sevoflurane and halothane for paediatric ambulatory anaesthesia. Br J Anaesth 1991; 67(4): 387-389. 9. LeDez K M, Lerman J. The minimum alveolar concentration (MAC) of isoflurane in preterm neonates. Anesthesiology 1987; 67: 301-307. 10. Lerman J, Robinson S, Willis M M, Gregory G A. Anesthetic requirements for halothane in young children 0-1 month and 1-6 months of age. Anesthesiology 1983; 59: 421-424. 11. Cameron C B, Robinson S, Gregory G A. The minimum anesthetic concentration of isoflurane in children. Anesthesiology 1984; 63: 418-420. 12. Taylor R H, Lerman J. Minimum Alveolar Concentration of desflurane and hemodynamic responses in infants and children. Anesthesiology 1991; 75: 975-979. 13. Murray D J, Mehta M P, Forbes R B, Dull D L. Additive contribution of nitrous oxide to halothane MAC in infants and children. Anesth Analg 1990; 71: 120-124. 14. Murray D J, Mehta M P, Forbes R B. The additive contribution of nitrous oxide to isoflurane MAC in infants and children. Anesthesiology 1991; 75: 186-190. 15. Fisher D M, Zwass M S. MAC of desflurane in 60% nitrous oxide in infants and children. Anesthesiology 1992; 76: 354-356. 16. Freisen R H, Henry D B. Cardiovascular changes in preterm neonates receiving isoflurane, halothane, fentanyl, and ketamine. Anesthesiology 1986; 64: 238-242. 17. Gallagher T M, Shields M D, Black G W. Isoflurane does not reduce aortic peak flow velocity in children. Br J Anaesth 1986; 58: 1116-1121. 18. Laird C R D, Mulholland D, Crean P M, Black G W. The effects of
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halothane and isoflurane on hand blood flow in children as determined by venous occlusion plethysmography. Paediatric Anaesthesia 1993; 3: 7%82. 19. Mulholland D, Laird C R D, Crean P M, Black G W. The effects of halothane and isoflurane on forearm blood flow in children (as determined by venous occlusion plethysmography). Paediatric Anaesthesia 1994; 4: 83-86. 20. Weiskopf R B, Eger E IlI, Holmes M A e t al. Epinephrineinduced premature ventricular contractions and changes in arterial blood pressure and heart rate during 1-653, isoflurane, and halothane anesthesia in swine. Anesthesiology 1989; 70(2): 293-298. 21. Karl H W, Swedlow D B, Lee K W, Downes J J. Epinephrinehalothane interactions in children. Anesthesiology 1983; 58: 142-145. 22. Zwass M S, Fisher D M, Welborn L G e t al. Induction and maintenance characteristics of anesthesia with desflurane and nitrous oxide in infants and children. Anesthesiology 1992; 76: 373-378. 23. Sampaio M M, Crean P M, Keilty S R, Black G W. Changes in oxygen saturation during inhalation induction of anaesthesia in children. Br J Anaesth 1989; 62: 199-201. 24. Moto R, Miyasaka K, Takata M, Kondo Y, Asahara S. Initial experience of complete switchover to sevoflurane in 1550 children. Paediatric Anaesthesia 1993; 3: 229-233. 25. Hatch D, Fletcher M. Anaesthesia and the ventilatory system in infants and young children. Br J Anaesth 1992; 68: 398-410. 26. Yamakage M, Tamiya K, Horikawa D, Sato K, Namiki A. Effects of halothane and sevoflurane on the paediatric respiratory pattern. Paediatric Anaesthesia 1994; 4: 53-56. 27. Pounder D R, Blackstock D, Steward D J. Tracheal extubation in children: Halothane versus isoflurane, anesthetized versus awake. Anesthesiology 1991; 74: 653-655. 28. Pittet J F, Melis A, Rouge J C, Morel D R, Gemperle G, Tassonyi E. Effect of volatile anaesthetics on vecuronium-induced neuromuscular blockade in children. Anesth Analg 1990; 70: 248-252. 29. Taylor R H, Lerman J. Induction, maintenance and recovery characteristics of desflurane in neonates, infants and children. Can J Anaesth 1992; 39: 6-13. 30. Leon J E, Bissonnette B. Cerebrovascular responses to carbon dioxide in children anaesthetized with halothane and isoflurane. Can J Anaesth 1991; 38: 817-825. 31. Eger E III. New Inhaled anaesthetics. Anesthesiology 1994; 80: 906-922.