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Newborn Anaesthesia: Pharmacological Considerations D $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
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