Download Toxicity of local anesthetic drugs: a pediatric

Pediatric Anesthesia ISSN 1155-5645
REVIEW ARTICLE
Toxicity of local anesthetic drugs: a pediatric perspective
Per-Arne Lönnqvist
Department of Physiology & Pharmacology, Karolinska Institute, Paediatric Anaesthesia & Intensive Care, Karolinska University Hospital,
Stockholm, Sweden
Keywords
child; age; adverse events; complications;
local anesthetics; drugs; lipid rescue
Correspondence
Per-Arne Lönnqvist,
Department of Physiology & Pharmacology,
Paediatric Anaesthesia & Intensive Care,
Karolinska University Hospital, Karolinska
Institute, Stockholm, Sweden
Email: [email protected]
Section Editor: Per-Arne Lönnqvist
Accepted 11 May 2011
doi:10.1111/j.1460-9592.2011.03631.x
Summary
The main mechanism of action of local anesthetics (LA) is to block sodium
channels, thereby interrupting the propagation of nerve impulses. However,
this action not only is localized to the sodium channels of nerve tissues
involved with pain transmission but will have its effect on any tissue containing sodium channels. Thus, if there is a rapid absorption into the systemic circulation of locally injected LA or if LA inadvertently is injected
into a blood vessel, then significant blockade of sodium channels in other
tissues may also be blocked and serious complications may ensue. The two
most important tissues associated with systemic toxicity of LA are the central nervous and the cardiovascular systems, which may lead to seizures,
tachyarrhythmias, and ultimately death from apnea and cardiovascular collapse. The aim of this communication is to elucidate some issues that are
associated with toxicity of LA and its treatment in the pediatric population.
Potency to cause systemic toxicity of different
local anesthetics (LA)
The binding of short-acting LA (SALA) to the sodium
channel is often characterized as ‘fast in-fast out’,
whereas long-acting LA (LALA) are known as ‘fast inslow out’. Thus, if systemic complication do occur, the
duration of the toxicity is much longer and more serious when using long-acting than short-acting compounds (Table 1) (1).
The difference between SALA and LALA can be
illustrated by a comparison between lidocaine and
racemic bupivacaine. In a seminal study, Reiz & Nath
(1) infused lidocaine or bupivacaine into the coronary
circulation of dogs. In line with the LA potency ratio
of 1 : 4 between lidocaine and bupivacaine, the effect
on cardiac contractility was also observed to be 1 : 4.
However, the effect on cardiac conductivity was found
to be 1 : 16, and the time to normalization of the electrocardiogram (EKG) was 6 and 48 min for lidocaine
and bupivacaine, respectively (Table 1). Based on these
data, it can be concluded that the potential for serious
toxicity of LALA is higher compared with SALA and
that the main negative cardiac effect of LALA is their
adverse influence on cardiac electrophysiology.
Pediatric Anesthesia 22 (2012) 39–43 ª 2011 Blackwell Publishing Ltd
Because of the quite pronounced potential for serious systemic toxicity of racemic bupivacaine, more
concentrated solutions than 0.5% are no longer commercially available. The more recently marketed alternatives to racemic bupivacaine, levo-bupivacaine, and
ropivacaine, have been shown to be associated with a
wider margin of safety compared with racemic bupivacaine. The relative safety of racemic bupivacaine,
levo-bupivacaine, and ropivacaine has been reported by
Santos & DeArmas and coworkers (2). The three various LALA were infused intravenously in nonpregnant
sheep, and the dose associated with symptoms of serious systemic toxicity was assessed. As is clearly shown
in Figure 1, the order of toxicity was found to be racemic bupivacaine > levo-bupivacaine > ropivacaine.
Thus, ropivacaine appears to be the least toxic of
the LALA. However, the study referred to above does
not take into account the relative LA potency of these
agents. Based on obstetric epidural studies, the minimal local anesthetic concentration of the three LALA
has been established and compared. Thus, racemic
bupivacaine and levo-bupivacaine have been found
equipotent (3), whereas ropivacaine was found to be
only 60% as potent as racemic bupivacaine (4).
Against this background, the wider safety margin
39
Toxicity of local anesthetic drugs
P.-A. Lönnqvist
Table 1 Relationship between racemic bupivacaine and lidocaine
according to Reiz & Nath (1). Reiz S, Nath S., Cardiotoxicity of local
anaesthetic agents, Br J Anaesth 1986; 58: 736–746, by permission
of Oxford University Press
Anesthetic potency: 4 : 1
Depression of cardiac contractility: 4 : 1
Prolongation of QRS complex: 16 : 1
Time to recover normal conduction (min): 48 vs 6
associated with ropivacine potentially can be explained
by a reduced LA potency compared with racemic bupivacaine and levo-bupivacaine. With regard to the relative toxicity of racemic bupivacaine and levobulivacaine, it has been shown that levo-bupivacaine
does bind to the cardiac sodium channel in a different
and more benign way compared with racemic bupivacaine (5), thereby explaining the fact that levo-bupivacaine is less cardiotoxic compared with racemic
bupivacaine.
The author’s conclusion concerning the aforesaid is
that levo-bupivacaine and ropivacaine are associated
with a reduced risk for serious systemic toxicity compared with racemic bupivacaine and should therefore
routinely be used in children (with the exception of
spinal anesthesia). However, in fact, whether ropivacaine is associated with a lower risk for systemic toxicity than levo-bupivacaine remains unclear. Thus, the
choice between these two more modern LALA can be
based on personal preference or market availability.
Dosage recommendations of LALA in children
During the resurge of interest in pediatric regional
anesthesia during the second half of the 1980s, no clear
knowledge existed with regard to the safe dosing of
racemic bupivacaine. Based on adult dosing, most centers used their own dosage regimens that often were
found to be excessive, as evidenced by a number of
case reports reporting both seizures and cardiac arrhythmias (6–8). This resulted in a large-scale American Patient Safety Foundation sponsored study that
ultimately was able to define safe dosage guidelines for
the use of racemic bupivacaine in newborns and older
children (Table 2) (9).
Because of the reduced systemic toxicity of levo-bupivacaine and ropivacaine, a common question is
whether it is possible to give an increased dose of these
agents compared with racemic bupivacaine and still be
within safe limits. This issue deserves to be divided
into two different parts. First, if a regional block does
not work after using the maximum dose defined for
racemic bupivacaine according to Table 2, it will not
work better if you inject an even larger quantity of
LALA. Thus, in this setting, it can be recommended to
adhere to the maximum dose of racemic bupivacaine
also when using levo-bupivacaine and ropivacaine to
avoid the risk of systemic toxicity and instead change
analgesic strategy (e.g., administer adjunct or change
to systemic analgesia).
To discuss the use of a total bolus dosage in excess
of 2.5 mg kg)1 is more valid in the situation where different regional anesthetic blocks are to be combined,
e.g., lumbar plexus and sciatic nerve blocks or lateral
and subcostal transverse abdominis plane blocks.
Bösenberg et al. (10) have reported the use of 3 mg
kg)1 of ropivacaine in children without observing
symptoms of systemic toxicity or plasma levels of ropivacaine in the range of potential risk for systemic
Nonpregnant
Bupivacaine
Ropivacaine
Levobupivacaine
0.05
***
***
0.04
(11.5)
mmol·kg–1
*
(11.3)
**
0.03
(11.9)
*
(11.3)
(10.9)
(9.9)
***
0.02
(9.2)
(9.0)
(8.1)
(6.7)
*
(5.9)
(4.4)
0.01
N=
12
12
13
Convulsions
40
9
7
11
Hypotension
7
7
Apnea
10
12
12
13
Circulatory collapse
Figure 1 Continuous intravenous infusion
of long-acting local anesthetics in nonpregnant sheep, Santos & DeArmas (2).
Reproduced from Santos AC, DeArmas PI.
Systemic toxicity of levobupivacaine, bupivacaine, and ropivacaine during continuous
intravenous infusion to nonpregnant and
pregnant ewes. Anesthesiology 2001; 95:
1256–1264, Wolters Kluwer Health.
Pediatric Anesthesia 22 (2012) 39–43 ª 2011 Blackwell Publishing Ltd
P.-A. Lönnqvist
Toxicity of local anesthetic drugs
Bolus injection
Neonates
Children
Continuous infusion
Neonates
Children
1.5–2.0 mg kg)1
2.5 mg kg)1
0.2 mg kg)1 h)1
0.4 mg kg)1 h)1
2
AAG concentration (mg·l–1)
Table 2 Dosage guidelines for racemic bupivacaine (9). Modified
from Berde CB, Toxicity of local anesthetics in infants and children.
J Pediatr 1993; 122: S14–S20, Elsevier
1.6
AAG = 0.512 + 0.162 age
1.2
Other group
Before surgery
48 h after surgery
0.8
0.4
AAG = 0.413 + 0.043 age
0
toxicity. Against this background, it may, in the setting
of combined blocks, be reasonable to allow the use of
3 mg kg)1 as a maximum dose of ropivacaine or levobupivacaine. However, if doing so, one must always
bear in mind that the plasma levels, depending on the
type of block, may be in the gray zone for systemic
toxicity (11,12).
Protein binding and the issue of the free fraction
of LA
Most LA, and especially LALA, are extensively subjected to plasma protein binding (PPB) (typical values
for protein binding of LALA are >90%). Unspecific
binding of LA occurs with many plasma proteins, with
albumin being the most important unspecific plasma
protein binder. Much more specific binding occurs to
the acute-phase protein alpha-1 acid glycoprotein
(orosomuciod; AAG), which is responsible for the
major PPB of LA.
Lerman et al. (13) have shown that AAG plasma
levels are low in newborns and toddlers and that normal adult values are not reached before 1 year of age.
This will, thus, result in an increased free fraction of
LA and thereby a potential for increased risk for systemic LA toxicity in newborns and infants.
Tucker, a main researcher and expert in the field of
PPB of LA, previously argued that reduced PPB
because of low levels of plasma proteins, including low
levels of AAG, did result is an important increased
risk for systemic toxicity. However, because the free
concentration of LA is in equilibrium with both the
fraction bound to plasma proteins and the fraction
bound to the tissues, there will be a dynamic interchange between these three compartments that may
ameliorate the potential adverse effects of reduced
AAG binding. Thus, Tucker later has modified and
moderated his view on the importance of PPB for the
occurrence of systemic LA toxicity (14). However, the
relative importance of this issue in small children is
still debated (15).
Furthermore, it should be noted that even newborns
are capable to react with a significant acute-phase
Pediatric Anesthesia 22 (2012) 39–43 ª 2011 Blackwell Publishing Ltd
Biliary atresia
Before surgery
48 h after surgery
2
4
Age (months)
6
8
Figure 2 Alpha-1 acid glycoprotein concentration vs age in the biliary atresia group (closed symbols) and the other group (open symbols) before surgery (circles) and 48 h after the operation
(triangles). The concentration increases in all infants after surgery.
(16). Reproduced from Meunier JF, Goujard E, Dubousset AM
et al. Pharmacokinetics of bupivacaine after continuous epidural
infusion in infants with and without biliary atresia. Anesthesiology
2001; 95: 87–95, Wolters Kluwer Health.
response when subjected to stress, thereby substantially
increasing their AAG levels, which in turn will increase
the binding capacity of LALA during continuous infusions (16) (Figure 2).
In summary, PPB of LA in neonates and infants is
reduced compared with older individuals, mainly
because of low levels of AAG, but the clinical significance of this reduction in PPB is still not clear.
Symptoms, signs, and treatment of systemic
toxicity in children
As the vast majority of pediatric patients are asleep
when the block is placed, early symptoms are not possible to detect. Thus, the first signs of toxicity in this
setting are seizures, tachyarrhythmias, or cardiovascular
collapse.
The use of a test dose (LA with added epinephrine)
is advocated by some authorities for the early identification of an inadvertent intravascular injection of LA.
However, it is important to realize that the test dose
will not provide any early warning signs of rapid
absorption of LA from the injection site.
Studies simulating intravascular injection with epinephrine-containing LA have investigated the sensitivity and specificity of the test dose. Various different
indicators or end points have been used, e.g., increase
in heart rate, increase in blood pressure, and changes
in T-wave configuration on the EKG (17–20). Unfortunately, the most informative clinical sign of intravascular injection is dependent on anesthetic technique
(20,21), and sensitivity and specificity values are not
conclusive enough to merit universal mandatory use.
Thus, practice with regard to mandatory use of a test
41
Toxicity of local anesthetic drugs
dose varies considerably between institutions as well as
countries, and its use appears to be linked, at least in
part, to the existing medicolegal situation.
Early signs of LA toxicity (e.g., alterations of mental
state and muscular twitching) may be possible to
detect if awake regional techniques are used (i.e.,
awake caudal blockade in ex-premature babies) (22) or
in the postoperative period if continuous infusion techniques are used. However, these signs are easily missed
or misinterpreted and may even be taken as signs of
inadequate pain-relief, resulting in either bolus dosing
or increasing the rate of the continuous infusion of
LA, thereby producing overt signs of systemic toxicity.
Thus, when faced with the clinical situation of unclear
postoperative problems in a child with an ongoing
infusion of LA, one should always consider whether
the symptoms may reflect early signs of systemic LA
toxicity or not.
Treatment algorithms of suspected or overt LA
toxicity are currently readily available http://www.
aagbi.org/publications/guidelines/docs/la_toxicity_2010.
pdf (23) (Figure 3). The most recent addition to the
treatment armamentarium of severe systemic LA toxicity is the Lipidrescue concept (24–26). The mechanism
behind the efficacy of this new treatment is still largely
unknown but a useful metaphor is the ‘Lipid sink’
(27). As LA are lipophilic drugs, it can be assumed
that the free unbound LA in the circulation will be
‘taken up’ by the lipid part of the plasma and thereby
being sequestered from having its effect. As there exists
an equilibrium between LA present in the blood and
the LA residing in the different body tissues (most
importantly the heart and the CNS), it can be
presumed that LA will move from the tissues to the
P.-A. Lönnqvist
blood and then again into the lipid component of
the plasma until a new equilibrium has been
established.
Recent animal experiments have suggested that the
efficacy of the Lipidrescue is influenced by the amount
of epinephrine used during resuscitation as well as by
the type of LALA. These studies point to Lipidrescue
being less effective if large doses of epinephrine has
been administered or if ropivacaine has been used
(28,29). However, these new data have so far not been
incorporated in treatment guidelines, and successful
resuscitation of ropivacaine toxicity has been reported
also in children (30).
The main current discussion is the time-point when
Lipidrescue should be instituted. Current algorithms
indicate that Lipidrescue should be used as a last
resort, whereas as early administration as possible is
being advocated by some researchers and clinicians as
the efficacy of Lipidrescue from a theoretical standpoint must be better before cardiovascular collapse has
already occurred (31). However, a recent study performed in piglets showed that epinephrine 3 lg kg)1 is
more effective than lipid if treatment is started before
cardiovascular collapse has already occurred (treatment started at 50% reduction in blood pressure) (32).
Thus, the efficacy of Lipidrescue may depend on when
it is administered during the course ultimately leading
to cardiovascular collapse.
In conclusion, Lipidrescue is a novel and effective
method to reverse serious systemic toxicity of LA.
With regard to the time-point when Lipid should be
started, it appears appropriate to administer it as soon
as it is available and not only to use it as a last resort.
However, it is important to remember that Lipidrescue
is not a substitute for normal resuscitation measures.
Local tissue toxicity
Figure 3 Suggested treatment with Intralipid in case of serious
systemic toxicity of local anesthetics according to the Association
of Anaesthetists of Great Britain and Ireland. For complete algorithm and comments, please see Weinberg, 2010 (23).
42
Although slightly beside the core of this text, it may be
prudent to remind the reader that LA, especially
LALA, may cause local tissue toxicity (most frequently
local muscle tissue necrosis) (33). Although no data
currently exist, it is reasonable to expect that the risk
increase with the use of more concentrated LALA. In
most patients, the occurrence of limited local muscle
necrosis may not be associated with more than localized pain that eventually will subside without longterm problems or sequelae.
So far, no pediatric case reports have been published
concerning this, but it can be speculated that premature babies and neonates may be a population at specific risk for this complication. Furthermore, in this
specific population, even moderate myonecrosis could
Pediatric Anesthesia 22 (2012) 39–43 ª 2011 Blackwell Publishing Ltd
P.-A. Lönnqvist
Toxicity of local anesthetic drugs
potentially produce myoglobinemia with concomitant
adverse renal effect.
No specific treatment for this complication of LALA
is currently available, but systemic analgesics and
physiotherapy appear to be logic treatment options. In
animal studies, local administration of beta-2 agonists
has been found to produce a positive effect (34) and
may potentially be used if the patient has a very severe
muscle necrosis deemed to be because of prior injection of LALA.
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