- Email: [email protected]
Paediatric anaesthesia – New drug developments
Vol. 2, No. 1 2005
Drug Discovery Today: Therapeutic Strategies Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Pain and anaesthesia
Paediatric anaesthesia – New drug developments Anil Visram*, David P. Stansfield Barts and The London NHS Trust, Royal London Hospital, Whitechapel Road, London, UK E1 1BB
New drugs are introduced to paediatric practice only after they have been used safely in adults. Occasionally unanticipated side effects emerge. We discuss some of
Section Editors: Brigitta Brandner and Lesley Bromley – University College London Hospital’s Trust, London, UK
these and how they can relate to the developmental regulation of neural transmission. We propose that drugs should be tested on paediatric animal models and clinical trials conducted in children so that side effects can be anticipated.
Introduction Drugs used in paediatric anaesthesia are introduced into adult practice before they are used in children, but their actions and side effects might be different in children. This can be due to pharmacokinetic variations but can also relate to the receptor and neural pathway development. In this review, we examine evidence that anaesthetic drugs can produce apoptotic cell death if administered during synaptogenesis and that nitrous oxide might be less effective and more toxic in infants and neonates. We will discuss the unexpected side effects that propofol and sevoflurane have in children. We assess evidence that effective and safe pain control in infants will only be achieved if developmental regulation of nocioceptive pathways is understood. We review new local anaesthetic agents and additives that can modify the effect of these agents in children.
Anaesthesia-induced developmental neuroapoptosis In rats, it was shown that anaesthetic drugs that act by blocking the N-methyl-D-aspartate (NMDA) receptor (nitrous *Corresponding author: A. Visram ([email protected]) 1740-6773/$ ß 2005 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2005.05.012
oxide) or by stimulating the gamma aminobutyric acid (GABAA) receptor (isoflurane, midazolam) could produce widespread apoptotic neurodegeneration in the developing brain [1]. Seven-day-old rats exposed to six hours of isoflurane exhibited dose-dependent neurodegeneration. Exposure to nitrous oxide or midazolam did not produce these effects as single agents but did in combination. This neurodegeneration affected the laterodorsal and anteroventral thalamic nuclei with 0.75% isoflurane; the parietal cortex (layer II) was only significantly affected at 1.5% isoflurane. The three agents together produced significantly greater apoptosis than isoflurane alone. In one-month-old rats, long-term potentiation in hippocampal slices showed profound suppression with a cocktail of isoflurane, nitrous oxide and midazolam, and behavioural studies showed impaired learning and memory processes [2]. The window of vulnerability is regarded to be the period of synaptogenesis, which lasts up to three weeks in rats, but might extend up to several years in humans [3]. How relevant are these rat models to human practice? From a developmental perspective, six hours exposure in a rat can be equivalent to several weeks in a human and drug doses might not be clinically relevant [4]. Withholding anaesthetic drugs that are currently used in neonates not only would increase intraoperative and postoperative complications but could also produce prolonged changes in the perception of pain [5,6]. www.drugdiscoverytoday.com
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Drug Discovery Today: Therapeutic Strategies | Pain and anaesthesia
Nitrous oxide Nitrous oxide is a gaseous anaesthetic agent that is still commonly used today. Apart from being involved in apoptotic cell death, nitrous oxide has other potentially toxic effects. It can inactivate vitamin B12 in prolonged use, thus inhibiting the activity of methionine synthetase. It has recently been implicated in the neurological deterioration of three infants [7]. Recent studies in rats suggest that noradrenergic inhibitory neurones, which can mediate the effects of nitrous oxide, are not present at birth and can take three weeks to develop [8]. Studies in Fischer rats showed, both behaviourally and histochemically, that adult nociceptive responses to nitrous oxide were not present in rats less than three weeks old [9]. A study in humans showed less analgesic effect with nitrous oxide than with a proprietary local anaesthetic cream (lignocaine–prilocaine emulsion) for venous cannulation in children aged one to four years old [10]. This lack of efficacy, combined with the potential for toxicity, suggests that we should avoid nitrous oxide in neonates.
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changes, although the clinical implications of these are not known [17]. Desflurane, which is contraindicated in inhalational induction, is not popular in paediatric anaesthesia because of airway irritability, although it has been used in high-risk ex-premature infants where rapid emergence is beneficial [18].
Propofol Propofol is a popular induction agent in paediatric anaesthetic practice. It has been used as total intravenous anaesthesia for many years. Although it can be used for maintenance of anaesthesia in children over one month old, it is not recommended for sedation in children under 17 following the deaths of patients in intensive care. They can develop a condition characterized by metabolic acidosis, myocardial failure, bradyarrhythmias, ketonuria, rhabdomyolisis and death. The mechanism is unknown, but reports show reduced cytochrome C oxidase activity suggesting impaired mitochondrial electron transport [19].
Neuronal signal transmission in neonates Xenon The advantages of using xenon as a substitute for nitrous oxide have been reviewed recently [11]. Xenon is thought to act by inhibiting NMDA receptors [12]. Two studies, looking at surrogate markers of neuronal injury, suggested that xenon might be neuroprotective. In a primary culture of neuronal and glial cells from the cerebral cortex of neonatal mice exposed to NMDA, glutamate or oxygen deprivation xenon was neuroprotective. Unlike other volatile agents, this occurred at subanaesthetic doses (IC50 concentrations being 19 and 28% atm for NMDA and glutamate-induced injury, respectively). In adult rats, xenon was neuroprotective without the dose-dependent toxicity exhibited by ketamine and nitrous oxide [13]. Although expensive, xenon has favourable kinetic, cardiac and neuroprotective qualities, which can make it useful in the future.
Newer volatile agents Sevoflurane has rapidly replaced halothane as the volatile agent of choice in paediatric anaesthesia. Its advantages include smooth induction, rapid emergence, minimal cardiovascular depression and few arrhythmias. Concerns about fluoride toxicity and toxic metabolite production with soda lime and baralyme have not proven to be clinically important [14]. Emergence delirium remains a concern. The evidence suggests that this is not related to rapid emergence [15] as previously thought. Fentanyl, midazolam and clonidine have all been used to attenuate its incidence and severity [16]. In a recent review, there have been some concerns that high dose sevoflurane (2 MAC or higher) can produce epileptiform EEG 60
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Differences between neuronal transmission in neonates and adults can be due to axonal myelination and synaptic transmission [20]. Synaptic differences involve immaturity of receptor function, neurotransmitter production and reuptake and reduced postsynaptic receptor density. There are three types of receptor in the excitatory pathway mediated by glutamate: alpha amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA), kainite (KA) and NMDA. There is developmental regulation of these receptors [21] and differences in both the density and protein constituents of all three receptors in the newborn compared with the adult. The NMDA receptor is particularly interesting because it is important in anaesthesia mechanisms, pain transmission and the development of chronic pain syndromes. It consists of several subunits and its function varies depending on which subunits are expressed. As subunit expression is dependent on synaptic activity, neonates can develop chronic pain syndromes if acute pain is not adequately treated. This is alluded to in clinical studies [22]. In adults, NMDA and AMPA receptors are found together. In newborn rat dorsal columns, there are so-called ‘silent neurones’: NMDA receptors without functional AMPA receptors. AMPA receptors facilitate normal pain transmission via C fibres. They only manifest later in development and the NMDA receptor is an important regulator of their expression [21]. Does this have a therapeutic implication? Ketamine, an NMDA receptor blocker, is more effective at reversing the chronic pain cycle in young rats [23]. But it is not clear how prolonged use of an NMDA blocker during this plastic period would affect AMPA receptor development, and whether this would affect normal neuronal function. Interpretation of the
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effect of ketamine is complicated because it acts on other receptors and further studies need be conducted using pure NMDA blockers.
Opioids and the new born Neonates are extremely sensitive to opioids. Pharmacokinetics provides part of the explanation, but there are pharmacodynamic differences in the density and pattern of opioid receptors compared with adults [24]. A recent study used calcium imaging and behavioural techniques to look at OP3 opioid receptors in the dorsal horn of newborn and adult rats [25]. In the adults, the majority of OP3 receptors were found on the presynaptic primary afferents of C and Ad fibres, whereas they were also found on the non-nociceptive large diameter Ab fibres in the newborn. The behavioural tests reflected this by showing that opioids had greater attenuation of mechanical reflexes and decreased attenuation of thermal reflexes. If this finding were true in human neonates, it might mean that mechanical endpoints incorporated into neonatal pain scoring systems are misleading [26]. Opioid administration can affect other sensory modalities as well as nociception, with possible effects on development. Codeine is a prodrug that is converted to morphine by cytochrome P450 enzyme CYP2D6. This metabolism is known to vary within and between populations, but a recent study in neonatal rats showed that codeine analgesia had low efficacy even in a rat model that extensively metabolized codeine in the early postnatal period. This might mean that codeine has poor efficacy in human neonates although this has not been shown in clinical studies [27].
Local anaesthetic agents Use of local anaesthetic agents in infants and neonates is increasing. Amides are the most commonly used long acting agents. They are potent sodium channel blocking drugs. Bupivacaine has been the most frequently used amide, with 30 years of clinical use. In toxic concentrations, it can cause seizures, dysrhythmias, transient neuropathic symptoms and cardiovascular collapse. Local anaesthetic toxicity has been extremely rare in infants and children, but there have been some reports following increased use of bupivacaine epidural infusions [28]. Infants and neonates have a greater risk of toxicity because of increased dose requirements and different pharmacokinetics.
Pharmacokinetics Amide anaesthetics are protein bound (bupivacaine and ropivacaine 95%), mainly to a-1-acid glycoprotein (AAG) and human serum albumin. Toxicity is related to the unbound fraction of the drugs, which is higher in neonates and infants due to decreased AAG compared with adults. They are metabolized by the cytochrome P450 system. Neither CYP3A4,
Drug Discovery Today: Therapeutic Strategies | Pain and anaesthesia
which metabolises bupivacaine, nor CYP1A2, which metabolises ropivacaine, is mature at birth [29]. The epidural space buffers the systemic absorption of amide anaesthetics, although the duration of this effect decreases with age [28]. In an infant less than six months old, ropivacaine achieves maximum plasma concentration in 90–120 minutes following a single dose; it only takes 30 minutes in a child more than eight years old. Plasma clearance is still maturing at birth, with the clearance of bupivacaine reaching two-thirds of adult levels at six months and ropivacaine reaching adult levels at five years.
Dosage To achieve a block of similar strength and duration, neonates require much higher doses than would be expected for their weight compared with adults [30]. This applies to both central and peripheral nerve blocks and has been confirmed in animal studies of spinal and sciatic nerve models. Raymond et al. [30] showed that the greater the length of nerve exposed to a local anaesthetic, the lower the concentration of drug within the nerve required to achieve a block. Because of the greater potential for bupivacaine toxicity in neonates, despite the use of lower concentrations (e.g. 0.1% infusions) other agents have been investigated.
Levobupivacaine Bupivacaine is a mixture of two stereoisomers. Aberg and Luduena found that in animals the S( ) isomer had a higher LD50 (the dose that killed half the animals) and a longer duration of action after skin infiltration [31]. In animal models, levobupivacaine is seven times less potent than dextrobupivacaine at blocking potassium channels (suggested to be involved with the cardiotoxicity of bupivacaine by QT prolongation), had less inhibitory effect on cardiac sodium channel currents (thus less slowing of cardiac conduction) and faster recovery (suggesting easier reversal of toxicity) [31]. In sheep, almost twice the dose of levobupivacaine was required (by direct intravenous infusion) to cause a fatal cardiac arrhythmia compared with bupivacaine [31]. In human adult volunteer studies, levobupivacaine tended to produce less QRS prolongation, less CNS symptoms (e.g. tinnitus) and less EEG excitation than bupivacaine [31]. Levobupivacaine seems to have similar efficacy to bupivacaine in both adults and children and has been used in peripheral and central nerve blocks successfully. Although levobupivacaine is only licensed for use in ilioinguinal and iliohypogastric nerve blocks in the UK, there is a growing body of evidence supporting its use in the epidural and caudal spaces.
Ropivacaine Ropivacaine is an S-enantiomer aminoamide local anaesthetic. It has less potential for toxicity than bupivacaine. www.drugdiscoverytoday.com
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The epidural buffering effect discussed earlier offsets the immature P450 enzyme and reduced clearance [32]. Total and free plasma ropivacaine concentrations following a single shot caudal with 0.2% ropivacaine are similar in infants to those found in adults [33]. Ropivacaine (0.2%) has a similar efficacy to 0.25% bupivacaine, but with less motor block. Ropivacaine is currently only licensed for caudal blocks in children in the UK.
Caudal additives Many drugs have been added to caudal local anaesthetic solutions to improve effect and decrease risk of toxicity [34,35]. Epinephrine appears to enhance analgesia when used with ropivacaine, but this can be an alpha effect. As an additive to detect intravascular injection a dose of 0.5 mg/kg has 100% specificity. It increases T-wave size by 10%, heart rate by ten beats per minute and systolic blood pressure by 15 mmHg with a latency of up to 90 seconds [36]. There is a theoretical risk of neurological complications such as anterior spinal artery syndrome. Opioids increase both duration and spread of caudal analgesia, but side effects such as pruritus and urinary retention limit use [35]. The risk of respiratory depression makes them unsuitable for ambulatory surgery. Clonidine is a partially selective a2 agonist. It has an analgesic and anaesthetic sparing action when used systemically and can minimize sevoflurane-induced delirium but its use is limited by sedation and hypotension. When preservative free clonidine is used in a caudal (it is not licensed for this route) its effect correlates with CSF and not plasma levels. It appears to stimulate pre and postsynaptic a2 receptors in the dorsal horn grey matter. A dose of 1–2 mg/kg can extend the duration of a bupivacaine caudal by up to 150 minutes. There have been two case reports of apnoeas in a neonate and a preterm infant. We concur with de Beer and Thomas’ [35] recommendation that clonidine should be avoided in infants. Ketamine is a phencyclidine derivative that acts as an NMDA receptor blocker. It is analgesic and anaesthetic when used systemically, but causes delirium and hallucinations, which can be alleviated with benzodiazepines. Preservative free ketamine 0.5 mg/kg given caudally (not a licensed route) significantly prolongs bupivacaine and ropivacaine blocks; 1 mg/kg leads to postoperative behavioural problems. This can be avoided by using the pure S-ketamine stereoisomer. Sketamine 1 mg/kg and clonidine 1 mg/kg have been shown to give analgesia as effective as 0.25% bupivacaine, thus avoiding the potential for local anaesthetic toxicity [37]. Neourotoxicity has been reported in animal studies when high dose ketamine (1.6 mg/kg) caused three deaths out of 33 animals. Long-term infusion of ketamine (seven days [38]) with preservative in a patient with chronic pain caused a lymphocytic vasculitis, although intrathecal use with and without pre62
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servative caused no neurological sequelae in other animal studies [35]. If there is a potential for neurological damage it is unclear whether it is the ketamine or its preservatives that are responsible. Midazolam appears to act at GABA-benzodiazepine binding sites especially in lamina II of the dorsal horn. In animal and adult studies it showed dose-dependent analgesia both intrathecally and epidurally, which shows partial reversal with naloxone. In children, 50 mg/kg midazolam with 0.125% bupivacaine caudally increased the duration of analgesia, compared with bupivacaine alone, but increased sedation [35]. Tramadol is licensed for systemic use in children over 12. When used caudally it appears to have no additive effect to bupivacaine and causes increased vomiting [39]. Neostigmine has been added to 0.2% ropivacaine caudals and decreases analgesic requirements and increases time to first analgesic [40]. We believe this is a promising additive and should be investigated further.
Conclusions Anaesthetic drugs (see Table 1) are tested and used in adults before being introduced in children. Currently, many anaesthetic drugs are used ‘off label’ (i.e. they are used in an age group or for an indication not specifically covered by the license). As this review has discussed, the effects of this might be unexpected with far reaching consequences. The potentially fatal side effects of propofol infusions in sick children and the emergence delirium from sevoflurane are unanticipated from adult studies. The work by Olney and co-workers on the neurotoxic effects of anaesthetics in neonates has sent tremors through the world of paediatric anaesthesia – does a general anaesthetic given to a neonate cause neurological damage? Recently, an understanding of developmental regulation of neural transmission has alerted us to possible differences in the action of analgesic drugs. Does their use in neonates and infants affect development? What is the answer to this dilemma? Clearly drugs that can be safely used in the paediatric population are needed and drug companies should be obliged to research paediatric safety and efficacy. But, the ethical and logistical constraints of clinical trials in children are extensive and are becoming ever more stringent. Identifying relevant animal models can be the first step and extended meticulous and formal drug surveillance can help. Many national regulatory bodies are now encouraging paediatric research. Initiatives like the FDA’s paediatric exclusivity provision grant a further six months patent to a drug that is tested on children. Innovations like this should be encouraged and extended. Researching drugs in children might be ethically difficult, but it is unethical not to try.
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Drug Discovery Today: Therapeutic Strategies | Pain and anaesthesia
Table 1. Drugs in paediatric anaesthetic practice Therapies
Targets (or mechanism of action)
Pros
Cons
Refs
Nitrous oxide
Noradrenergic inhibitory neurones suggested
Analgesia > 3 weeks old
Vitamin B12 inactivation
[8–10]
Xenon
Inhibition of NMDA receptors
Neuroprotection
Expensive
[9,11]
Sevoflurane
Smooth, rapid induction and emergence. CVS stability
Emergence delirium. Epileptiform EEG
[15,17]
Desflurane
Rapid emergence in exprem infants
Airway irritability. Contraindicated in induction
[18]
Propofol infusion syndrome
[19]
Propofol Ropivacaine
Cytochrome C oxidase Sodium channels
TIVAa b
[29]
b
[28]
Decreased cardiotoxicity
Levobupivacaine
Sodium channels
Decreased cardiotoxicity
Caudal additives Epinephrine
a,b Adrenoceptors
Test for Intravascular injection
Risk of neurological complications
[32]
Clonidine
Alpha 2 receptors in dorsal horn grey matter
Increased caudal duration
Apnoeas in neonates
[33]
Ketamine
NMDA receptors
Increased caudal duration
Potential for neurotoxicity and behavioural disturbance
[32]
Midazolam
Dorsal horn GABA
Increased caudal duration
Sedation
[32]
Ref. [32] is a review article. Consult for further references. a Total intravenous anaesthesia. b Compared with bupivacaine.
References 1 Ikonomidou, C. et al. (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283, 70–74 2 Vesna, J-T. et al. (2003) Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J. Neurosci. 23, 876 3 Dobbing, J. and Sands, J. (1979) The brain growth spurt in various mammalian species. Early Hum. Dev. 3, 79–84 4 Olney, J.W. et al. (2004) Anesthesia-induced developmental neuroapoptosis. Does it happen in humans? Anesthesiology 101, 273–275 5 Anand, K.J.S. (1993) Relationships between stress responses and clinical outcome in newborns, infants and children. Crit. Care Med. 21, S358–S359 6 Taddio, A. et al. (2002) Conditioning and hyperalgesia in newborns exposed to repeated heel lances. JAMA 288, 857–861 7 Litman, R.S. (2004) Nitrous oxide: the passing of a gas? Curr. Opin. Anaesthesiol. 17, 207–209 8 Fitzgerald, M. et al. (1986) The functional development of descending inhibitory pathways in the dorsolateral funiculus of the newborn rat spinal cord. Brain Res. 389, 261–270 9 Ohashi, Y. et al. (2002) Nitrous oxide exerts age dependent antinocioceptive effects in Fischer rats. Pain 100, 7–18 10 Gall, O. et al. (1999) Relative effectiveness of lignocaine–prilocaine emulsion and nitrous oxide inhalation for routine preoperative laboratory testing. Paediatr. Anaesth. 9, 305–310 11 Sanders, R.D. et al. (2003) Xenon: no stranger to anaesthesia. Br. J. Anaesth. 91, 709–717 12 Franks, N.P. et al. (1998) How does xenon produce anaesthesia? Nature 396, 324 13 Ma, D. et al. (2002) Neuroprotective and neurotoxic properties of the inert gas xenon. Br. J. Anaesth. 89, 739–746 14 Gentz, B.A. and Malan, T.P. (2001) Renal toxicity with sevoflurane: a storm in a teacup? Drugs 61, 2155 15 Cohen, I.T. et al. (2003) Rapid emergence does not explain agitation following sevoflurane anaesthesia in infants and children; a comparison with propofol. Paediatr. Anaesth. 13, 63–67
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Lerman, J. (2004) Inhalational anaesthetics. Paediatr. Anaesth. 14, 380–383 Constant, I. et al. (2005) Sevoflurane and epileptiform EEG changes. Paediatr. Anaesth. 15, 266–274 Sale, S. et al. (March 2005) A prospective comparison of sevoflurane and desflurane in formerly premature infants undergoing inguinal herniorrhaphy. Association of Paediatric Anaesthetists of Great Britain and Ireland Conference, Norwich. Bray, R.J. (1998) Propofol infusion syndrome in children. Paediatr. Anaesth. 8, 491–499 Kretz, F.J. and Reimann, B. (2003) Ontogeny of receptors relevant to anaesthesiology. Curr. Opin. Anaesthesiol. 16, 281–284 Pattinson, D. and Fitzgerald, M. (2004) The neurobiology of infant pain; development of excitatory and inhibitory neurotransmission in spinal dorsal horn. Reg. Anaesth. Pain Med. 29, 36–44 Taddio, A. et al. (1997) Effect of neonatal circumcision on pain response during subsequent routine vaccination. Lancet 349, 599–603 DeLima, J. et al. (2004) The postnatal development of ketamine analgesia – an electrophysiological study in rat pups. Proceedings of the IXth World Congress on Pain, Seattle.p. 411, IASP Press Bouwmeester, N.J. et al. (2003) Age and therapy related effects on morphine requirements and plasma concentrations of morphine and its metabolites in postoperative infants. Br. J. Anaesth. 90, 642–652 Nandi, R. et al. (2004) The functional expression of Mu opioid receptors on sensory neurones is developmentally regulated. Morphine analgesia is less selective in the newborn. Pain 111, 35–50 Van Dijk, M. et al. (2000) The reliability and validity of the COMFORT scale as a postoperative pain instrument in 0 to 3-year-old infants. Pain 84, 367– 377 Williams, D.G. et al. (2004) Developmental regulation of codeine analgesia in the rat. Anaesthesiology 100, 92–97 Mazoit, J.X. and Dalens, B.J. (2004) Pharmacokinetics of local anaesthetics in infants and children. Clin. Pharmacokinet. 43, 17–32 Berde, C. (2004) Local anaesthetics in infants and children: an update. Pediatr. Anesth. 14, 387–393 Raymond, S.A. et al. (1989) The role of length of nerve exposed to local anesthetic in impulse blocking action. Anesth. Analg. 68, 563–570
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31 32 33 34
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McCleod, G.A. and Burke, D. (2001) Levobupivacaine. Anaesthesia 56, 331–341 Mazoit, J.X. and Dalens, B.J. (2003) Ropivacaine in infants and children. Curr. Opin. Anaesthesiol. 16, 305–307 Hansen, T.G. et al. (2001) Caudal ropivacaine in infants: population pharmacokinetics and plasma concentrations. Anesthesiology 94, 579–584 Ansermino, M. et al. (2003) Nonopioid additives to local anaesthetics for caudal blockade in children: a systematic review. Paediatr. Anaesth. 13, 561–573 de Beer, D.A.H. and Thomas, M.L. (2003) Caudal additives in children – solutions or problems? Br. J. Anaesth. 90, 487–498 Tobias, J.D. (2001) Caudal epidural block: a review of test dosing and recognition of systemic injection in children. Anesth. Analg. 93, 1156–1161
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Hager, H. et al. (2002) Caudal clonidine prolongs analgesia from caudal S(+)-ketamine in children. Anesth. Analg. 94, 1169–1172 Stotz, M. et al. (1999) Histological findings after long-term infusion of intrathecal ketamine for chronic pain: a case report. J. Pain Symptom Manage. 18, 223–228 Gunduz, M. et al. (2001) A comparison of single dose caudal tramadol, tramadol plus bupivacaine and bupivacaine administration for postoperative analgesia in children. Paediatr. Anaesth. 11, 323–326 Turan, A. et al. (2003) Caudal ropivacaine and neostigmine in pediatric surgery. Anesthesiology 98, 719–722
Drug Discovery Today: Therapeutic Strategies Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Pain and anaesthesia
Paediatric anaesthesia – New drug developments Anil Visram*, David P. Stansfield Barts and The London NHS Trust, Royal London Hospital, Whitechapel Road, London, UK E1 1BB
New drugs are introduced to paediatric practice only after they have been used safely in adults. Occasionally unanticipated side effects emerge. We discuss some of
Section Editors: Brigitta Brandner and Lesley Bromley – University College London Hospital’s Trust, London, UK
these and how they can relate to the developmental regulation of neural transmission. We propose that drugs should be tested on paediatric animal models and clinical trials conducted in children so that side effects can be anticipated.
Introduction Drugs used in paediatric anaesthesia are introduced into adult practice before they are used in children, but their actions and side effects might be different in children. This can be due to pharmacokinetic variations but can also relate to the receptor and neural pathway development. In this review, we examine evidence that anaesthetic drugs can produce apoptotic cell death if administered during synaptogenesis and that nitrous oxide might be less effective and more toxic in infants and neonates. We will discuss the unexpected side effects that propofol and sevoflurane have in children. We assess evidence that effective and safe pain control in infants will only be achieved if developmental regulation of nocioceptive pathways is understood. We review new local anaesthetic agents and additives that can modify the effect of these agents in children.
Anaesthesia-induced developmental neuroapoptosis In rats, it was shown that anaesthetic drugs that act by blocking the N-methyl-D-aspartate (NMDA) receptor (nitrous *Corresponding author: A. Visram ([email protected]) 1740-6773/$ ß 2005 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2005.05.012
oxide) or by stimulating the gamma aminobutyric acid (GABAA) receptor (isoflurane, midazolam) could produce widespread apoptotic neurodegeneration in the developing brain [1]. Seven-day-old rats exposed to six hours of isoflurane exhibited dose-dependent neurodegeneration. Exposure to nitrous oxide or midazolam did not produce these effects as single agents but did in combination. This neurodegeneration affected the laterodorsal and anteroventral thalamic nuclei with 0.75% isoflurane; the parietal cortex (layer II) was only significantly affected at 1.5% isoflurane. The three agents together produced significantly greater apoptosis than isoflurane alone. In one-month-old rats, long-term potentiation in hippocampal slices showed profound suppression with a cocktail of isoflurane, nitrous oxide and midazolam, and behavioural studies showed impaired learning and memory processes [2]. The window of vulnerability is regarded to be the period of synaptogenesis, which lasts up to three weeks in rats, but might extend up to several years in humans [3]. How relevant are these rat models to human practice? From a developmental perspective, six hours exposure in a rat can be equivalent to several weeks in a human and drug doses might not be clinically relevant [4]. Withholding anaesthetic drugs that are currently used in neonates not only would increase intraoperative and postoperative complications but could also produce prolonged changes in the perception of pain [5,6]. www.drugdiscoverytoday.com
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Drug Discovery Today: Therapeutic Strategies | Pain and anaesthesia
Nitrous oxide Nitrous oxide is a gaseous anaesthetic agent that is still commonly used today. Apart from being involved in apoptotic cell death, nitrous oxide has other potentially toxic effects. It can inactivate vitamin B12 in prolonged use, thus inhibiting the activity of methionine synthetase. It has recently been implicated in the neurological deterioration of three infants [7]. Recent studies in rats suggest that noradrenergic inhibitory neurones, which can mediate the effects of nitrous oxide, are not present at birth and can take three weeks to develop [8]. Studies in Fischer rats showed, both behaviourally and histochemically, that adult nociceptive responses to nitrous oxide were not present in rats less than three weeks old [9]. A study in humans showed less analgesic effect with nitrous oxide than with a proprietary local anaesthetic cream (lignocaine–prilocaine emulsion) for venous cannulation in children aged one to four years old [10]. This lack of efficacy, combined with the potential for toxicity, suggests that we should avoid nitrous oxide in neonates.
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changes, although the clinical implications of these are not known [17]. Desflurane, which is contraindicated in inhalational induction, is not popular in paediatric anaesthesia because of airway irritability, although it has been used in high-risk ex-premature infants where rapid emergence is beneficial [18].
Propofol Propofol is a popular induction agent in paediatric anaesthetic practice. It has been used as total intravenous anaesthesia for many years. Although it can be used for maintenance of anaesthesia in children over one month old, it is not recommended for sedation in children under 17 following the deaths of patients in intensive care. They can develop a condition characterized by metabolic acidosis, myocardial failure, bradyarrhythmias, ketonuria, rhabdomyolisis and death. The mechanism is unknown, but reports show reduced cytochrome C oxidase activity suggesting impaired mitochondrial electron transport [19].
Neuronal signal transmission in neonates Xenon The advantages of using xenon as a substitute for nitrous oxide have been reviewed recently [11]. Xenon is thought to act by inhibiting NMDA receptors [12]. Two studies, looking at surrogate markers of neuronal injury, suggested that xenon might be neuroprotective. In a primary culture of neuronal and glial cells from the cerebral cortex of neonatal mice exposed to NMDA, glutamate or oxygen deprivation xenon was neuroprotective. Unlike other volatile agents, this occurred at subanaesthetic doses (IC50 concentrations being 19 and 28% atm for NMDA and glutamate-induced injury, respectively). In adult rats, xenon was neuroprotective without the dose-dependent toxicity exhibited by ketamine and nitrous oxide [13]. Although expensive, xenon has favourable kinetic, cardiac and neuroprotective qualities, which can make it useful in the future.
Newer volatile agents Sevoflurane has rapidly replaced halothane as the volatile agent of choice in paediatric anaesthesia. Its advantages include smooth induction, rapid emergence, minimal cardiovascular depression and few arrhythmias. Concerns about fluoride toxicity and toxic metabolite production with soda lime and baralyme have not proven to be clinically important [14]. Emergence delirium remains a concern. The evidence suggests that this is not related to rapid emergence [15] as previously thought. Fentanyl, midazolam and clonidine have all been used to attenuate its incidence and severity [16]. In a recent review, there have been some concerns that high dose sevoflurane (2 MAC or higher) can produce epileptiform EEG 60
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Differences between neuronal transmission in neonates and adults can be due to axonal myelination and synaptic transmission [20]. Synaptic differences involve immaturity of receptor function, neurotransmitter production and reuptake and reduced postsynaptic receptor density. There are three types of receptor in the excitatory pathway mediated by glutamate: alpha amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA), kainite (KA) and NMDA. There is developmental regulation of these receptors [21] and differences in both the density and protein constituents of all three receptors in the newborn compared with the adult. The NMDA receptor is particularly interesting because it is important in anaesthesia mechanisms, pain transmission and the development of chronic pain syndromes. It consists of several subunits and its function varies depending on which subunits are expressed. As subunit expression is dependent on synaptic activity, neonates can develop chronic pain syndromes if acute pain is not adequately treated. This is alluded to in clinical studies [22]. In adults, NMDA and AMPA receptors are found together. In newborn rat dorsal columns, there are so-called ‘silent neurones’: NMDA receptors without functional AMPA receptors. AMPA receptors facilitate normal pain transmission via C fibres. They only manifest later in development and the NMDA receptor is an important regulator of their expression [21]. Does this have a therapeutic implication? Ketamine, an NMDA receptor blocker, is more effective at reversing the chronic pain cycle in young rats [23]. But it is not clear how prolonged use of an NMDA blocker during this plastic period would affect AMPA receptor development, and whether this would affect normal neuronal function. Interpretation of the
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effect of ketamine is complicated because it acts on other receptors and further studies need be conducted using pure NMDA blockers.
Opioids and the new born Neonates are extremely sensitive to opioids. Pharmacokinetics provides part of the explanation, but there are pharmacodynamic differences in the density and pattern of opioid receptors compared with adults [24]. A recent study used calcium imaging and behavioural techniques to look at OP3 opioid receptors in the dorsal horn of newborn and adult rats [25]. In the adults, the majority of OP3 receptors were found on the presynaptic primary afferents of C and Ad fibres, whereas they were also found on the non-nociceptive large diameter Ab fibres in the newborn. The behavioural tests reflected this by showing that opioids had greater attenuation of mechanical reflexes and decreased attenuation of thermal reflexes. If this finding were true in human neonates, it might mean that mechanical endpoints incorporated into neonatal pain scoring systems are misleading [26]. Opioid administration can affect other sensory modalities as well as nociception, with possible effects on development. Codeine is a prodrug that is converted to morphine by cytochrome P450 enzyme CYP2D6. This metabolism is known to vary within and between populations, but a recent study in neonatal rats showed that codeine analgesia had low efficacy even in a rat model that extensively metabolized codeine in the early postnatal period. This might mean that codeine has poor efficacy in human neonates although this has not been shown in clinical studies [27].
Local anaesthetic agents Use of local anaesthetic agents in infants and neonates is increasing. Amides are the most commonly used long acting agents. They are potent sodium channel blocking drugs. Bupivacaine has been the most frequently used amide, with 30 years of clinical use. In toxic concentrations, it can cause seizures, dysrhythmias, transient neuropathic symptoms and cardiovascular collapse. Local anaesthetic toxicity has been extremely rare in infants and children, but there have been some reports following increased use of bupivacaine epidural infusions [28]. Infants and neonates have a greater risk of toxicity because of increased dose requirements and different pharmacokinetics.
Pharmacokinetics Amide anaesthetics are protein bound (bupivacaine and ropivacaine 95%), mainly to a-1-acid glycoprotein (AAG) and human serum albumin. Toxicity is related to the unbound fraction of the drugs, which is higher in neonates and infants due to decreased AAG compared with adults. They are metabolized by the cytochrome P450 system. Neither CYP3A4,
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which metabolises bupivacaine, nor CYP1A2, which metabolises ropivacaine, is mature at birth [29]. The epidural space buffers the systemic absorption of amide anaesthetics, although the duration of this effect decreases with age [28]. In an infant less than six months old, ropivacaine achieves maximum plasma concentration in 90–120 minutes following a single dose; it only takes 30 minutes in a child more than eight years old. Plasma clearance is still maturing at birth, with the clearance of bupivacaine reaching two-thirds of adult levels at six months and ropivacaine reaching adult levels at five years.
Dosage To achieve a block of similar strength and duration, neonates require much higher doses than would be expected for their weight compared with adults [30]. This applies to both central and peripheral nerve blocks and has been confirmed in animal studies of spinal and sciatic nerve models. Raymond et al. [30] showed that the greater the length of nerve exposed to a local anaesthetic, the lower the concentration of drug within the nerve required to achieve a block. Because of the greater potential for bupivacaine toxicity in neonates, despite the use of lower concentrations (e.g. 0.1% infusions) other agents have been investigated.
Levobupivacaine Bupivacaine is a mixture of two stereoisomers. Aberg and Luduena found that in animals the S( ) isomer had a higher LD50 (the dose that killed half the animals) and a longer duration of action after skin infiltration [31]. In animal models, levobupivacaine is seven times less potent than dextrobupivacaine at blocking potassium channels (suggested to be involved with the cardiotoxicity of bupivacaine by QT prolongation), had less inhibitory effect on cardiac sodium channel currents (thus less slowing of cardiac conduction) and faster recovery (suggesting easier reversal of toxicity) [31]. In sheep, almost twice the dose of levobupivacaine was required (by direct intravenous infusion) to cause a fatal cardiac arrhythmia compared with bupivacaine [31]. In human adult volunteer studies, levobupivacaine tended to produce less QRS prolongation, less CNS symptoms (e.g. tinnitus) and less EEG excitation than bupivacaine [31]. Levobupivacaine seems to have similar efficacy to bupivacaine in both adults and children and has been used in peripheral and central nerve blocks successfully. Although levobupivacaine is only licensed for use in ilioinguinal and iliohypogastric nerve blocks in the UK, there is a growing body of evidence supporting its use in the epidural and caudal spaces.
Ropivacaine Ropivacaine is an S-enantiomer aminoamide local anaesthetic. It has less potential for toxicity than bupivacaine. www.drugdiscoverytoday.com
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The epidural buffering effect discussed earlier offsets the immature P450 enzyme and reduced clearance [32]. Total and free plasma ropivacaine concentrations following a single shot caudal with 0.2% ropivacaine are similar in infants to those found in adults [33]. Ropivacaine (0.2%) has a similar efficacy to 0.25% bupivacaine, but with less motor block. Ropivacaine is currently only licensed for caudal blocks in children in the UK.
Caudal additives Many drugs have been added to caudal local anaesthetic solutions to improve effect and decrease risk of toxicity [34,35]. Epinephrine appears to enhance analgesia when used with ropivacaine, but this can be an alpha effect. As an additive to detect intravascular injection a dose of 0.5 mg/kg has 100% specificity. It increases T-wave size by 10%, heart rate by ten beats per minute and systolic blood pressure by 15 mmHg with a latency of up to 90 seconds [36]. There is a theoretical risk of neurological complications such as anterior spinal artery syndrome. Opioids increase both duration and spread of caudal analgesia, but side effects such as pruritus and urinary retention limit use [35]. The risk of respiratory depression makes them unsuitable for ambulatory surgery. Clonidine is a partially selective a2 agonist. It has an analgesic and anaesthetic sparing action when used systemically and can minimize sevoflurane-induced delirium but its use is limited by sedation and hypotension. When preservative free clonidine is used in a caudal (it is not licensed for this route) its effect correlates with CSF and not plasma levels. It appears to stimulate pre and postsynaptic a2 receptors in the dorsal horn grey matter. A dose of 1–2 mg/kg can extend the duration of a bupivacaine caudal by up to 150 minutes. There have been two case reports of apnoeas in a neonate and a preterm infant. We concur with de Beer and Thomas’ [35] recommendation that clonidine should be avoided in infants. Ketamine is a phencyclidine derivative that acts as an NMDA receptor blocker. It is analgesic and anaesthetic when used systemically, but causes delirium and hallucinations, which can be alleviated with benzodiazepines. Preservative free ketamine 0.5 mg/kg given caudally (not a licensed route) significantly prolongs bupivacaine and ropivacaine blocks; 1 mg/kg leads to postoperative behavioural problems. This can be avoided by using the pure S-ketamine stereoisomer. Sketamine 1 mg/kg and clonidine 1 mg/kg have been shown to give analgesia as effective as 0.25% bupivacaine, thus avoiding the potential for local anaesthetic toxicity [37]. Neourotoxicity has been reported in animal studies when high dose ketamine (1.6 mg/kg) caused three deaths out of 33 animals. Long-term infusion of ketamine (seven days [38]) with preservative in a patient with chronic pain caused a lymphocytic vasculitis, although intrathecal use with and without pre62
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servative caused no neurological sequelae in other animal studies [35]. If there is a potential for neurological damage it is unclear whether it is the ketamine or its preservatives that are responsible. Midazolam appears to act at GABA-benzodiazepine binding sites especially in lamina II of the dorsal horn. In animal and adult studies it showed dose-dependent analgesia both intrathecally and epidurally, which shows partial reversal with naloxone. In children, 50 mg/kg midazolam with 0.125% bupivacaine caudally increased the duration of analgesia, compared with bupivacaine alone, but increased sedation [35]. Tramadol is licensed for systemic use in children over 12. When used caudally it appears to have no additive effect to bupivacaine and causes increased vomiting [39]. Neostigmine has been added to 0.2% ropivacaine caudals and decreases analgesic requirements and increases time to first analgesic [40]. We believe this is a promising additive and should be investigated further.
Conclusions Anaesthetic drugs (see Table 1) are tested and used in adults before being introduced in children. Currently, many anaesthetic drugs are used ‘off label’ (i.e. they are used in an age group or for an indication not specifically covered by the license). As this review has discussed, the effects of this might be unexpected with far reaching consequences. The potentially fatal side effects of propofol infusions in sick children and the emergence delirium from sevoflurane are unanticipated from adult studies. The work by Olney and co-workers on the neurotoxic effects of anaesthetics in neonates has sent tremors through the world of paediatric anaesthesia – does a general anaesthetic given to a neonate cause neurological damage? Recently, an understanding of developmental regulation of neural transmission has alerted us to possible differences in the action of analgesic drugs. Does their use in neonates and infants affect development? What is the answer to this dilemma? Clearly drugs that can be safely used in the paediatric population are needed and drug companies should be obliged to research paediatric safety and efficacy. But, the ethical and logistical constraints of clinical trials in children are extensive and are becoming ever more stringent. Identifying relevant animal models can be the first step and extended meticulous and formal drug surveillance can help. Many national regulatory bodies are now encouraging paediatric research. Initiatives like the FDA’s paediatric exclusivity provision grant a further six months patent to a drug that is tested on children. Innovations like this should be encouraged and extended. Researching drugs in children might be ethically difficult, but it is unethical not to try.
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Drug Discovery Today: Therapeutic Strategies | Pain and anaesthesia
Table 1. Drugs in paediatric anaesthetic practice Therapies
Targets (or mechanism of action)
Pros
Cons
Refs
Nitrous oxide
Noradrenergic inhibitory neurones suggested
Analgesia > 3 weeks old
Vitamin B12 inactivation
[8–10]
Xenon
Inhibition of NMDA receptors
Neuroprotection
Expensive
[9,11]
Sevoflurane
Smooth, rapid induction and emergence. CVS stability
Emergence delirium. Epileptiform EEG
[15,17]
Desflurane
Rapid emergence in exprem infants
Airway irritability. Contraindicated in induction
[18]
Propofol infusion syndrome
[19]
Propofol Ropivacaine
Cytochrome C oxidase Sodium channels
TIVAa b
[29]
b
[28]
Decreased cardiotoxicity
Levobupivacaine
Sodium channels
Decreased cardiotoxicity
Caudal additives Epinephrine
a,b Adrenoceptors
Test for Intravascular injection
Risk of neurological complications
[32]
Clonidine
Alpha 2 receptors in dorsal horn grey matter
Increased caudal duration
Apnoeas in neonates
[33]
Ketamine
NMDA receptors
Increased caudal duration
Potential for neurotoxicity and behavioural disturbance
[32]
Midazolam
Dorsal horn GABA
Increased caudal duration
Sedation
[32]
Ref. [32] is a review article. Consult for further references. a Total intravenous anaesthesia. b Compared with bupivacaine.
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