Editor- we read with interest the editorial written by Dr Drasner1
accompanying a review which considered the many potential causes of failed
spinal anaesthesia.2 While the majority of these are pharmacokinetic in
nature, Drasner cited two papers in support of a pharmacodynamic cause,
namely a genetically acquired resistance to local anaesthetic drugs.3,4
Both describe mutations in genes encoding voltage-gated Na+ channel α
subunits (these are large proteins comprising 24 membrane spanning
segments arranged in 4 repetitive domains D1-4, which combine in a
symmetrical fashion to form a central Na+ channel pore). The inherited
N395K mutation (the replacement of asparagine 395 by lysine, within the
sixth segment of D1), occurring in the human SCN9A gene encoding the
NaV1.7 channel is associated with reduced local anaesthetic sensitivity in
electrophysiological experiments performed in vitro.
Drasner’s suggestion that mutations in Na+ channel genes could
contribute to failure of spinal anaesthesia is intriguing, and appears
logical based upon the electrophysiological evidence. However, the N395K
mutation is rare and is easily identified in patients because they have
erythromelalgia (a rare, debilitating and painful neuropathic condition).
Further, the suggestion of a pharmacodynamic cause of failed spinal
anaesthesia raises two questions.
First, are there Na+ channel mutations that affect local anaesthetic
potency in otherwise asymptomatic individuals? In our opinion the most
likely answer to this is no. A search of the literature to date reveals
that synthetic mutations affecting the sensitivity of Na+ channels to
local anaesthetics in electrophysiological experiments are associated with
altered channel function.5,6 Mutations in the presumed local anaesthetic
binding site cause profound changes in channel function likely to be
associated with behavioural phenotypes such as erythromelalgia. However
our understanding of the local anaesthetic binding site remains incomplete
and it is possible that mutations affecting residues required for binding
may be otherwise asymptomatic.
Second, will reduced local anaesthetic sensitivity observed in vitro
be sufficiently profound to cause failed anaesthesia in vivo? It is
important to note that resistance to local anaesthetics induced by
mutations in Na+ channel genes has so far only been demonstrated in vitro.
Even a substantial decrease in the affinity of local anaesthetic binding
to the Na+ channel may not be clinically significant if sufficient local
anaesthetic reaches the effector site.
In short, it is not beyond the realms of possibility that relatively
asymptomatic individuals could have mutations in genes encoding voltage
gated Na+ channels that reduce the potency of local anaesthetic agents.
However, any such mutation is likely to be exceedingly rare, and is
unlikely to explain fairly frequent accounts of patients with local
anaesthetic resistance. Any physician who encounters such a patient should
therefore be encouraged to consider all the possible mechanisms of
failure.
P. D. W. Fettes1*
J-R. Jansson2
J. A. W. Wildsmith1
T. G. Hales1
1Dundee, UK.
2Södertälje, Sweden.
*paulfettes@nhs.net
Refs
1. Drasner K. Spinal anaesthesia: a century of refinement, and failure is
still an option. Br J Anaesth 2009; 102: 729-30
2. Fettes PDW, Jansson J-R, Wildsmith JAWW. Failed spinal anaesthesia:
mechanisms, management and prevention. Br J Anaesth 2009; 102:
3. Catterall WA, Dib-Hajj S, Meisler MH, Pietrobon D. Inherited neuronal
ion channelopathies: new windows on complex neurological diseases. J
Neurosci 2008; 28: 11768-77
4. Sheets PL, Jackson JO, Waxman SG, Dib-Hajj SD, Cummins TR. A Nav1.7
channel mutation associated with hereditary erythromyelgia contributes to
neuronal hyperexcitability and displays reduced lidocaine sensitivity. J
Physiol 2007; 581: 1019-31
5. Ulbricht W. Sodium channel inactivation: molecular determinants and
modulation. Physiol Rev 2005; 85: 1271-1301
6. Browne LE, Blaney FE, Yusaf SP, Clare JJ, Wray D. Structural
determinants of drugs acting on the Nav1.8 channel. J Biol Chem 2009; 284:
10523-10536
Conflict of Interest:
Dr Jansson works for AstraZeneca.
