Editorial

Does anaesthesia harm the developing brain –evidence or speculation?

ANDREW DAVIDSON M B B S , F A N Z C A , G R A D . D I P . E P I . B I O S T A TM B B S , F A N Z C A , G R A D . D I P . E P I . B I O S T A T*

AND SULPICIO SORIANO M D , F A A PM D , F A A P†

*Department of Anaesthesia, Royal Children’s Hospital, University of Melbourne, Australia and†Children’s Hospital Boston, Harvard Medical School, USA

It is not uncommon for the paediatric anaesthetist

to be confronted with an anxious parent requesting

assurance that an anaesthetic will not harm their

newborn child. From a parent’s perspective this is

not an unusual request. Anaesthesia seems a signi-

ficant event. Especially, when they have been con-

stantly mindful of habits, foods, chemicals and drugs

that could impair their unborn child’s development.

We usually reassure that barring a catastrophe,

recovery will be full and swift. The drugs will all

be gone without trace. But do we underestimate their

worry and is there really no cause for concern?

Animal studies have suggested that anaesthesia is

indeed harmful to newborns. In 1985, Uemura et al.

reported that prolonged exposure to halothane

(8 hÆday)1 for 5 days) resulted in a decreased syn-

aptic density and stunted behavioural development

(1). In 1999, the lay press seized the issue after a

provocative paper in Science. Ikonomidou et al.

reported that N-methyl DD-aspartate (NMDA) block-

ade resulted in significant apoptosis (programmed

cell death) in newborn rat brain (2). MK801, an

NMDA antagonist produced widespread apoptosis,

observed maximally in 7-day-old rats. Ketamine

(20 mgÆkg)1) was injected seven times over 9 h

producing similar results. This study has a number

of limitations (3). Of particular importance is the lack

of any physiological monitoring, the high doses

required, the relatively long exposure and the

questionable significance of apoptosis to long-term

development. Some degree of apoptosis is a normal

part of brain development. Hayashi et al. demon-

strated accelerated apoptosis after 9 h of repeated

doses, but no changes after a single dose of ketamine

(4). Significantly, they reported a decrease in weight

gain in the repeated dose group. The effects of

malnutrition on brain development also need to be

considered.

Ketamine and halothane are not the only drugs to

cause alarm. Agents such as ethanol, phencyclidine,

nitrous oxide, isoflurane, propofol, barbiturates,

diazepam, clonazepam and several other anticon-

vulsants, all increase apoptotic neurodegeneration in

developing rat brain (5–8). In addition to NMDA

blockade, gamma-aminobutyric acid receptor acti-

vation also triggers apoptosis. Fortunately (or unfor-

tunately depending on your perspective) the risks

may not be confined to fetuses and neonates. The

same researchers have demonstrated significantly

greater nitrous oxide and ketamine neurotoxicity in

the adult, rather than infant, rat, albeit via another

mechanism of cell death. (9)

The issue has resurfaced after Jevtovic-Todorovic

and colleagues recently published another study

addressing the risks of anaesthesia in neonatal rats.

(10) Seven-day-old rats were exposed for 6 h

to nitrous oxide, midazolam or isoflurane, either

alone in differing concentrations or in combination.

Nitrous oxide and midazolam alone caused no

apoptosis. Isoflurane produced significant apoptosis.

A cocktail of 75% nitrous oxide, 0.75% isoflurane

and 9 mgÆkg)1 of midazolam produced the greatest

apoptosis. The cocktail rats also demonstrated later

memory and learning impairment.

The authors describe this cocktail as a clinically

relevant anaesthesia protocol. For several reasons it

is not: compared with human use, the dose of

midazolam is very high. This reflects the interspecies

difference in the dose required for an anaesthetic

Correspondence to: Andrew Davidson, Department of Anaesthesia,Royal Children’s Hospital, Parkville 3052, VIC, Australia (email:andrew.davidson@rch.org.au).

Pediatric Anesthesia 2004 14: 199–200

� 2004 Blackwell Publishing Ltd 199

effect. It is questionable, whether the toxicity of such

high doses can be extrapolated to human beings as

the rats did not have the same degree of monitoring

that anaesthetized human neonates receive. For

issues of nutrition and fluid balance, there was no

indication that cerebral perfusion or oxygenation

was maintained. Only one measure was made for

the physiological status of the control and anaes-

thetized groups. This set of blood gases taken after

anaesthesia did show more hypoxia in the anaes-

thetized group. It is also unclear how well the

mother welcomed the treated pups back into the

litter. Of greatest concern is the length of exposure. It

is always problematic to compare animal develop-

ment with the longer and more complex human

development. Rat brains develop over approxi-

mately 2 weeks – a human brain develops over

several years. Six hours to a neonatal rat is equiv-

alent to a month in a human infant. Indeed it is rare

that we fully anaesthetize an infant for such a long

period. The closest to such an experience could be

infants on ECMO but even they are rarely com-

pletely anaesthetized. If the average neonatal anaes-

thetic were 1–2 h, then that would equate to less

than a minute in a rat. This is still considerably

shorter than the period used in Hayashi’s single-

dose experiment (4).

Although the animal data may not be applicable

to human beings, it would be imprudent to ignore it.

Evidence must be sought from human data. This is

not easy. A randomized control trial is unethical,

confounders abound and the outcome measures are

hard to define. Nevertheless, cohort studies investi-

gating outcome for neonates have been performed.

One study has suggested an adverse neurological

outcome, associated with surgery and general anaes-

thesia (11). This study followed a cohort of ELBW

infants (<1000 gm birth weight) and assessed their

sensorineural outcome at 5 years. Having surgery

and anaesthesia was a risk independent of the

general health of the infant. The authors do concede

that there could be unidentified confounders. In

particular, they cannot control for the risks of

transferring such small babies to another centre for

surgery. Transportation poses a considerable risk

from handling, fasting, changes in temperature,

hyperoxia or hypoxia. It is not possible to draw

conclusions until more relevant cohorts are exam-

ined to clarify the risks of anaesthesia alone.

There is another vital issue. What are the alterna-

tives to anaesthesia? Pain and the stress response are

associated with adverse outcome (12,13). If surgery

is required, anaesthesia is better than no anaesthesia.

We could ask which anaesthetic is best, but most

anaesthetics have been implicated. The apoptotic

potential of opioids is unknown. Could we delay

surgery, and if so till when? Given the prolonged

human development phase, surgery would have to

be delayed by months to years – usually not a

practical option. If any statements are to be presen-

ted about the putative harms of anaesthesia, they

need to be coupled with the realities of the benefits

of anaesthesia.

References1 Uemura E, Levin ED, Bowman RE. Effects of halothane on

synaptogenesis and learning behavior in rats. Exp Neurol 1985;89: 520–529.

2 Ikonomidou C, Bosch F, Miksa M et al. Blockade of NMDAreceptors and apoptotic neurodegeneration in the developingbrain. Science 1999; 283: 70–74.

3 Berde C, Cairns B. Developmental pharmacology acrossspecies: promise and problems. Anesth Analg 2000; 91: 1–5.

4 Hayashi H, Dikkes P, Soriano SG. Repeated administration ofketamine may lead to neuronal degeneration in the developingrat brain. Paediatr Anaesth 2002; 12: 770–774.

5 Ikonomidou C, Bittigau P, Ishimaru M et al. Ethanol-inducedapoptotic neurodegeneration and fetal alcohol syndrome.Science 2000; 287: 1056–1060.

6 Ikonomidou C, Bittgau P, Koch C et al. Neurotransmitters andapoptosis in the developing brain. Biochem Pharmacol 2001; 62:

401–405.7 Olney JW, Wozniak DF, Jevtovic-Todorovic V et al. Drug-

induced apoptotic neurodegeneration in the developing brain.Brain Path 2002; 12: 488–498.

8 Bittigau P, Sifringer M, Genz K et al. Antiepileptic drugs andapoptotic neurodegeneration in the developing brain. ProcNatl Acad Sci USA 2002; 99: 15089–15094.

9 Jevtovic-Todorovic V, wozniak DF, Benshoff ND, Olney JW. Acomparative evaluation of the neurotoxic properties of keta-mine and nitrous oxide. Brain Res 2001; 895: 264–267.

10 Jevtovic-Todorovic V, Hartman RE, Izumi Y et al. Earlyexposure to common anesthetic agents causes widespreadneurodegeneration in the developing rat brain and persistentlearning deficits. J Neurosci 2003; 23: 876–882.

11 The Victorian Infant Collaborative Study Group. Surgery andthe tiny baby: sensorineural outcome at 5 years of age. JPaediatr Child Health 1996; 32: 167–172.

12 Anand KJS, Sippell WG, Aynsley-Green A. Randomised trialof fentanyl anaesthesia in preterm babies undergoing surgery:effects on the stress response. Lancet 1987; 1: 243–247.

13 Anand KJS, Sippel WG, Schofield NM et al. Does halothaneanaesthesia decrease the stress response of newborn infantsundergoing operation? Br Med J 1988; 296: 668–672.

Accepted 22 April 2003

200 A. DAVIDSON AND S. SORIANO

� 2004 Blackwell Publishing Ltd, Pediatric Anesthesia, 14, 199–200