$38 REFRESHER COURSE OUTLINE

Newborn anaesthesia: pharmacological considerations D. Ryan Cook MD

Inhalation anaesthetics Several investigators have studied the age-related For the inhalation anaesthetics there are age-related cardiovascular effects of the potent inhalation differences in uptake and distribution, in anaes- anaesthetics at known multiples of MAC. At thetic requirements as reflected by differences in end-tidal concentrations of halothane bracketing MAC, in the effects on the four determinants of MAC, Lerman er al. 2 noted no difference in the cardiac output (preload, afterload, heart rate and incidence of hypotension or bradycardia in neonates contractility), and in the sensitivity of protective and in infants one to six months of age. Likewise, cardiovascular reflexes (e.g., baroreceptor reflex). we 3 have noted no age-related differences in the These differences limit the margin of safety of the determinants of cardiac output in developing piglets potent agents in infants. 1-20 days during either halothane or isoflurane Alveolar uptake of inhalation anaesthetics and anaesthesia. Halothane produced hypotension by a hence whole-body uptake is more rapid in infants reduction in contractility and heart rate; in much than in adults. J Lung washout is more rapid in older animals halothane also decreases peripheral infants than in adults because of the larger ratio vascular resistance. In piglets although blood pres- between alveolar minute ventilation and lung sure was equally depressed with isoflurane and volume (FRC) (3.5:1 in the infant vs. 1.3:1 in the halothane, cardiac output was better preserved adult). Increased brain size (ml.kg-J), limited during isoflurane anaesthesia. muscle mass, limited fat content, and proportional In awake man or animals decreases in blood differences in the distribution of cardiac output pressure are compensated for by an increase in heart contribute to differences in uptake. Age-related rate, myocardial contractility, and peripheral vas- differences in tissue partition coefficients also cular resistance. Potent inhalation anaesthetics de- influence the equilibrium tissue concentration and press baroreceptor reactivity in a concentration the rate of change in the tissue concentration. Early dependent manner. In infants or newborn animals in an anaesthetic induction (at equal inspired con- baroreceptor reflexes are more depressed (at equi- centrations) the infant will have higher tissue potent anaesthetic concentrations) than in older concentrations in brain, heart, and muscle than will animals. 4'5 This further limits the safety of potent the adult. anaesthetics in infants. Moreover, Cook et al. 6 MAC, an estimate of anaesthetic requirement, is, have demonstrated that the cardiovascular index for in part, age related. 2 Neonates require 25 per cent halothane is smaller in younger animals than in less anaesthetic than infants; infants have a greater older animals. The cardiovascular index is a reflec- anesthetic requirement than older patients. MAC is tion of the therapeutic index (i.e., the ratio between dramatically lower in newly born animals than in the anaesthetic concentration at cardiovascular col- their 12-hour-old counterparts. The response of the lapse to that of anaesthesia). newborn to painful stimuli is attenuated even in the Thus, potent inhalation anaesthetics must be used awake state. Most likely this is related to the with caution in newborns and infants. Because of immaturity of the central nervous system; elevated concentrations of progesterone and 13-endorphin and 13-1ipoproteins may also play a role in the University of Pittsburgh School of Medicine, Children's decrease in MAC in neonates. Hospital of Pittsburgh, Pittsburgh, Pennsylvania.

CAN ANAESTH SOC J 1986 / 33:3 / ppS38-$42 Cook: NEWBORN ANAESTHESIA: PHARMACOLOGICAL CONSIDERATIONS $39 the reduced margin of safety paediatric anaesthe- arterial pressure and systemic vascular resistance tists frequently favour nitrous-oxide-relaxants an- index were noted by Hickey et al. 13 Other indexes aesthesia (reinforced with small doses of narcotics). of cardiac function were unchanged. Schieber et For that reason a discussion of the clinical use of al.'4 documented that the cardiovascular effects of narcotics and muscle relaxants is, likewise, appro- fentanyl (without relaxant) are concentration- priate. dependent; a similar relationship between decreases in systolic blood pressure and concentration was Ketamine noted by Koren et al. 15 Respiratory depression is On al.~g.kg -I basis the amount of ketamine, a likely concentration-related. nonbarbiturate cyclohexamine derivative, required Several new analogs of fentanyl are undergoing to prevent gross movements is four times greater in clinical trials. Sufentanil is about seven times more infants under six months than in six-year-olds. 7 potent than fentanyl and has minimal cardiovascu- Acute studies show little metabolism of ketamine lar effects. Bradycardia is an uncommon feature. by the newborn. Recently, we determined the Hickey and Hansen 16 studied the cardiovascular pharrnacokinetics of ketamine in different-aged effects of sufentanil (5 - 10 p.g. kg- 1)_pancuronium patients. In infants less than three months of age the in infants with complex congenital heart disease. volume of distribution was similar to that in older Mean arterial blood pressure and heart rate declined infants but the elimination half-life was prolonged. mildly. We (unpublished data) have seen more Hence, clearance was reduced in the younger profound bradycardia and hypotension in such infants. Reduced metabolism and renal excretion in infants when sufentanil (151~g.kg -1) was given the young infant are the likely causes. In the with metocurine. Blood pressure responses to "anaesthetic" state associated with ketamine, respi- incision/sternotomy were more attenuated at the ration and blood pressure are usually well main- higher dose of sufentanil; humoral responses to tained. However, use of ketamine in infants, has stimulation were minimal. The phamaacokinetic been associated with respiratory depression and profile of sufentanil in infants is comparable to that apnoea, generalized extensor spasm with opistho- of fentanyl.~7 Alfentanil is equally potent to fen- tonus, an increase in intracranial pressure, and tanyl but has a shorter duration of action. Because acute increases in pulmonary artery pressure. of its relatively short duration of action alfentanil may be particularly useful in neonatal anaesthesia. Fentanyls Unfortunately, this has not been studied. The dose of fentanyl needed to guarantee satis- factory anaesthesia for infants is unknown. Age- related differences in the kinetics and sensitivity to Muscle relaxants fentanyl and changes in kinetics associated with Throughout childhood there is physical and bio- profound pathophysiologic conditions make gener- chemical maturation of neuromuscular junction, alizations difficult. S-ll However, in the neonate change in the contractile properties of skeletal fentanyl clearance seems comparable to that of the muscle, and an increase in the relative amount of older child or adult; fentanyl clearance is markedly muscle as a proportion of body weight. There are reduced in the premature infant. The elimination also changes in the apparent volume of distribution half-life is prolonged in neonates and in premature of relaxants, possible changes in their metabolism, infants. These marked variations in kinetics reflect and changes in their redistribution and excretion. age differences and perhaps differences in anaes- These factors influence dose-response relation- thetic, dose, and duration of sampling. We noted ships of muscle relaxants in infants and children. J8 that in infants having cardiac surgery fentanyl (50 ixg.kg-') was not uniformly effective in blunt- Depolarizing muscle relaxants ing cardiovascular responses nor hormonal respon- On a weight basis, infants require more succinyl- ses to surgery despite rather uniform fentanyl plasma choline than older children or adults to produce concentrations. The cardiovascular effects of fen- apnoea, depress respiration, or to depress neuro- tanyl at doses of 30-75 I.Lg'kg-' (with pancuron- muscular transmission (EMG or twitch). The esti- ium) are minimal. 12 Modest decreases in mean mated ED95 for succinylcholine in infants is 2.0 $40 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL mg.kg -I. Following an "intubating" dose of suc- following intramuscular succinylcholine. Atropine cinylcholine infants do not develop a phase II block (0.1 mg) appears to offer adequate protection (as defined by the criteria of Lee). Tachyphylaxis to against these bradyarrhythmias in all age groups. succinylcholine occurs in infants with a cumulative Recently, we j9 have seen several young infants dose of 4.0mg'kg -1 and phase LI block occurs at who developed fulminant pulmonary oedema fol- 6.0mg'kg-l; tachyphylaxis and a phase II block lowing intramuscular succinylcholine (4 mg.kg-~). occur at lower cumulative doses in older infants and The pulmonary oedema occurred within minutes of children. Although the infant has about one-half the the intramuscular injection; the pulmonary oedema plasmaebolinesterase concentration of the adult, at responded to continuous positive pressure ventila- equipotent doses of succinylcholine the recovery tion (CPAP). We speculate that this may represent a time is not prolonged in infants. haemodynamic form of pulmonary oedema from an When succinyleholine was given in equal doses acute elevation of systemic vascular resistance and on a surface area basis (40mg.m-2), there was no an acute decrease in pulmonary vascular resistance; difference between infants and adults in the times to in addition, "leaky" capillaries appear to be in- recover to 10, 50, 90 per cent neuromuscular volved. transmission; this dose of succinylcholine produced complete neuromuscular blockade in all patients. A Non-depolarizing muscle relaxants linear relationship exists between the log dose on a It has been suggested that the newborn is sensitive mg.m -2 basis and the maximum intensity of neuro- to d-tubocurarine (dTc), particularly in the first ten muscular blockade for infants, children, and adults. days of life. there is no increased sensitivity of hand In addition, there is a similar linear relationship muscles to dTc in infants as compared to adults. between the logarithm of the dose on a mg.m -z Likewise, there is no difference in the magnitude of basis and to either 50 or 90 per cent recovery times neuromuscular blockade from 0.22 mg.kg- ~of dTc for infants and children as a combined group. in infants under four months and those older than Because of its relatively small molecular size four months of age. However, in infants respiratory succinyleholine is rapidly distributed throughout depression parallels the neuromuscular blockade the extracellular fluid. The blood volume and extra- noted in the hands; in adults neuromuscular block- cellular (ECF) volume of the infant are significantly ade of the hand occurs prior to respiratory depres- greater than the child's or adult's on a weight basis. sion. This important observation suggests that the Therefore, on a weight basis (mg.kg -l) the infant respiratory muscle of the infant may be more requires about twice as much succinylcholine to sensitive to dTc than those of the adult, or that the produce 50 per cent neuromuscular blockade as do infant has less respiratory reserve than the adult. In adults. Since ECF and surface area bear a nearly actuality both may be true. Recent studies have constant relationship throughout life (6-8 L.m -2) it re-examined this issue. During halothane anaesthe- is not surprising that there is a good correlation sia the mean dose ofdTc required to produce 95 per between succinylcholine dose (in mg.m -2) and cent twitch depression and the time to recovery response throughout life. Redistribution and meta- from 95 per cent block (5 per cent neurotransmis- bolism of succinylcholine obviously determine the sion, T5) to 75 per cent block (25 per cent block (5 recovery times. Redistribution of succinylcholine per cent neurotransmission, T5) to 75 per cent block from a relatively small muscle mass into a relatively (25 per cent neurotransmission, T25) or to 50 per large ECF volume appears to rapidly terminate the cent block (50 per cent neurotransmission, T50) neuromuscular blocking effects of succinylcholine. was the same in infants and children. 2~ However, In the infant and small child profound sustained there was a wide range irt the EDgs for dTc in the sinus bradycardia (rates of 50 to 60/minute) is newborns (0.15-0.62 mg'kg-I). Thus, some new- commonly observed; rarely, asystole occurs. borns are quite sensitive and some are relatively Arrhythmias are more common following a second resistant to dTc. dose of succinylcholine. Nodal rhythm and ven- The ED95 for dTc in adults during nitrous tricular ectopic beats are seen in about 80 per cent of oxide-oxygen-narcotic anaesthesia is comparable to children given a single intravenous injection of that noted in the infants and children during succinylcholine; such arrhythmias are rarely seen halothane anaesthesia. Since halothane potentiates Cook: NEWBORN ANAESTHESIA" PHARMACOLOGICAL CONSIDERATIONS $41 dTc neuromuscular blockade these data suggest that children was similar to that of adults. At equipotent infants and children are resistant to dTc on a weight doses gallamine, pancuronium, dTc, and meto- basis. I subsequently estimated the ED95 for dTc on curine have, obviously, significantly prolonged a I~g'm-2 basis in infants, children, and adults recovery times compared to atracurium and vecuro- during halothane anaesthesia. The estimated ED9s nium. Renal clearance of these relaxants or their for dTc in neonates was 4 i~g.m-2; in children and metabolites is probably limited in the first several adults it was 7-8 I~g'm-z. Thus, the newborn is months of life since GFR is limited. Atracurium indeed sensitive to dTc when allowance is made for which spontaneously decomposes has a shorter differences in the volume of distribution for re- recovery time in infants than adults; vecuronium laxants and comparisons between age groups are which is metabolized has a longer recovery time in made during comparable types and depth of anaes- infants than adults. thesia. Keon and Dowries (unpublished data) compared Likewise, the ED95 (mg'kg -1) for metocurine, 21 changes in heart rate, changes in blood pressure, pancuronium, z2 and gallamine and the time to and differences in intubating conditions in infants recover from T5-T25 were comparable in infants (average age 5.6 months) "anaesthetized" with and children. Most likely, infants are likewise nitrous oxide-oxygen followed either dTc (0.6 sensitive to these relaxants on a ixg.m -2 basis. We mg.kg- 1) or pancuronium (0.1 mg'kg- 1). None had have determined the ED95 for atracurium, a non- received premedication. In both groups there were depolarizing relaxant of intermediate duration, in modest increases in pulse rate; transient episodes of adolescents, children, and infants during halothane bradycardia occurred in some infants in both groups anaesthesia using single dose curves. On a weight during intubation. No infant given pancuronium basis (l~g-kg -1) the ED95 of atracurium in infants developed significant hypotension or hypertension is comparable to that of adolescents; the ED95 of (greater than ten per cent change from control both are less than that of children. 23'24 Goudsouzian, levels). In contrast, 25 per cent of the infants given using cumulative dose curves noted no difference in dTc experienced decreases in blood pressure greater the ED95 for atracurium between adolescents and than ten per cent from control (range 11-26 per children. 2s On a p,g'm -2 basis the ED95 for infants cent). We noted minimal effects of atracurium, is about half that of adolescents or children. At gallamine, or pancuronium on the heart rate in equipotent doses the recovery times of neuromuscu- infants. Unless the heart rate had slowed from lar transmission in infants are comparable to that halothane neither gallamine nor pancuronium ex- noted in children; in both groups the recovery hibited any vagolytic effects. At equipotent doses times are more rapid than those of adults. We have (1 • ED95) in older children gallamine increases also noted that"light" isoflurane anaesthesia but not the heart rate twice that seen from pancuronium. "light" halothane anaesthesia potentiates atracurium These cardiovascular effects may be desirable in the (i.e., decreases the ED95) when compared to nitrous younger child or infant during halothane. Neither oxide-thiopentone-fentanyl. This has been con- metocurarine, atracurium, or vecuronium have firmed by continuous infusion studies where the rate significant cardiovascular effects at 2 • ED95. of atracurium infusion (l~g.kg-i.min -1) is decreased by isoflurane anaesthesia when compared to the rate References during balanced anaesthesia. 1 Brandom BW, Brandom RB, Cook DR. Uptake Goudsouzian et al. determined the ED9~ for and distribution of halothane in infants: in vivo vecuronium, another non-depolarizing relaxant of measurements and computer simulations. Anesth intermediate duration, in adolescents and children Analg 1983; 62: 404-10. during halothane anaesthesia. 26 Children had a 2 Lerman J, Robinson S, Willis MM, Gregory GA. higher ED95 than that measured in adolescents. Anesthetic requirement for halothane in young chil- Fisher and Miller noted no statistical difference in dren 0-1 month and 1-6 months of age. Anes- the EDso for vecuronium between infants, chil- thesiology 1983; 59: 421-4. dren, and adults. 27 At equipotent doses of vecuro- 3 Boudreaux P, Schieber RA, Cook DR. Hemo- nium the recovery time was prolonged in infants as dynamic effects of halothane in the newborn piglet. compared to children or adults; the recovery in Anesth Analg 1984; 63: 731-7. $42 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL

4 Ware R, Robinson S, Gregory GA. Effect of halo- 18 CookDR. Muscle relaxants in infants and children. thane on the baroreceptor response in newborn and Anesth Analg 1981; 60: 335-40. adult rabbits. Anesthesiology 1982; 56: 188-91. 19 Cook DR, Westman HR, Rosenfetd L, Hendershot 5 Duncan P, Gregory GA, Wade JA. The effects of RJ. Pulmonary edema in infants: possible associa- nitrous oxide on the baroreceptor response of new- tion with intramuscular succinylcholine. Anesth born and adult rabbits. Can Anesth Soc J 1981; 28: Analg 1981; 60: 220-3. 339-41. 20 Goudsouzian NG, Donlon JV, Savarese JJ, Ryan 6 Cook DR, 8random BW, Shiu G, Wolfson B. The JF. Re-evaluation of dosage and duration of action inspired median effective dose, brain concentration of d-tubocurarine in the pediatric age group. Anes- at anesthesia, and cardiovascular index for halothane thesiology 1975; 43: 416-25. in young rats. Anesth Analg 1981; 60: 182-5. 21 Goudsouzian NG, Liu L, Savarese JJ. Metocurine 7 CookDR. Pediatric anesthetic pharmacology: a re- in infants and children. Anesthesiology 1978; 49: view. Drugs 1976; 12: 212. 226-9. 8 Koehntop D, Rodman J, Brundage D, Hegland M, 22 Goudsouzian NG, Ryan JF, Savarese JJ. The Buckley J. Pharmacokinetics of fentanyl in neo- neuromuscular effets of pancuronium in infants and nates. Anesthesiology 1984; 61: A439. children. Anesthesiology 1974; 41:95-8. 9 Singleton MA, Rosen Jl, Fisher DM. Pharmacoki- 23 Brandom BW, Rudd GD, Cook DR. Clinical phar- netics of fentanyl for infants and adults. Anes- macology of atracurium (BW33A) in paediatric pa- thesiology 1984; 61: A440. tients. Br J Anaesth 1983; 55:117S-121S. 10 Johnson KL, Erickson JP, Holley FO, Scott JC. 24 Brandom BW, Woelfel SK, Cook DR, Fehr B, Rudd Fentanyl pharmacokinetics in the pediatric popula- D. Clinical pharmacology of atracurium in infants. tion. Anesthesiology 1984; 61: A441. Anesth Analg 1984; 63: 309-12. 11 Collins G, Koren G, Crean P, Klein J, Ray WL, 25 Goudsouzian NG, Liu LMP, Cote CJ, Gionfriddo MacLeod SM. The correlation between fentanyl M, Rudd GD. Safety and efficacy of atracurium in pharmacokinetics and pharmacodynamics in preterm adolescents and children anesthetized with halo- infants during PDA ligation. Anesthesiology 1984; thane. Anesthesiology (in press). 61: A442. 26 Goudsouzian NG, Martyn J, Liu LMP, Giofriddo 12 Hickey PR, Hansen DD. Fentanyl and sufentanil- M. Safety and efficacy of vercuronium in adoles- oxygen-pancuronium anesthesia for cardiac surgery cents and children. Anesth Analg (in press). in infants. Anesth Analg 1984; 63:117-24. 27 Fisher DM, Miller RD. Neuromuscular effects of 13 Hickey PR, Hansen DD, Wessell D. Responses to vecuronium (ORGNC45) in infants and children dur- high dose fentanyl in infants: pulmonary and ing N20, halothane anaesthesia. Anesthesiology (in systemic hemodynamics. Anesthesiology 1984; 61: press). A445. 14 Schieber RA, Stiller RL, Cook DR. Cardiovascular and pharmacodynamic effects of high-dose fentanyl in newborn piglets. Anesthesiology 1985; 63: 166- 71. 15 Koren G, Crean P, Goresky G, Klein J, MacLeod SM. Fentanyl anesthesia for cardiac surgery in chil- dren: a) fentanyl-oxygen vs. fentanyl-N~O; b) rela- tionship between drug concentrations and pharmaco- dynamics. Anesthesiology 1984; 61: A444. 16 Hickey PR, Hansen DD. Fentanyl and sufentanil- oxygen-pancuronium anesthesia for cardiac surgery in infants. Anesth Analg 1984; 63: 117-24. 17 Davis PJ, Robinson KA, Stiller RL, Cook DR. Sufentanil kinetics in infants and children. Anesthe- siology 1985; 63: A472.