Correspondence
| 935
Fig 2 Entropy response to muscle relaxation with rocuronium.
Fig 1 Increase in both Response entropy (RE) and State entropy (SE) with
wearing of muscle relaxation as indicated by Train-of-Four (TOF) ratio.
increase can in fact be because of EMG interference in the case of
both the RE and SE parameters and titration of anaesthetic agents
should not be based solely using these indices. This observed
artifact in the SE reading is probably because of the fact that
EMG activity contains some frequencies below 32 Hz.5 6
Declaration of interest
None declared.
References
1. Viertio-Oja H, Maja V, Sarkela M, et al. Description of the
entropy algorithm as applied in the Datex-Ohmeda S/5
Entropy Module. Acta Anaesthesiol Scand 2004; 48: 154–61
2. Mathews DM, Cirullo PM, Struys MM, et al. Feasibility study for
the administration of remifentanil based on the difference
between response entropy and state entropy. Br J Anaesth
2007; 98: 785–91
3. Liu N, Chazot T, Huybrechts I, Law-Koune JD, Barvais L,
Fischler M. The influence of a muscle relaxant bolus on bispectral and datex-ohmeda entropy values during propofol–
remifentanil induced loss of consciousness. Anesth Analg
2005; 101: 1713–8
4. Hans P, Giwer J, Brichant JF, Dewandre PY, Bonhomme V. Effect
of an intubation dose of rocuronium on spectral entropy and
bispectral indexTM responses to laryngoscopy during propofol
anaesthesia. Br J Anaesth 2006; 97: 842–7
5. Kawaguchi M, Takamatsu I, Kazama T. Rocuronium dosedependently suppresses the spectral entropy response to tracheal intubation during propofol anesthesia. Br J Anaesth 2009;
102: 667–72
6. Aho AJ, Lyytikainen LP, Yli-Hankala A, Kamata K, Jantti V.
Explaining Entropy responses after a noxious stimulus, with
or without neuromuscular blocking agents, by means of the
raw electroencephalographic and electromyographic characteristics. Br J Anaesth 2011; 106: 69–76
doi:10.1093/bja/aev385
The significant contribution of the partitioning effect in lipid
resuscitation for bupivacaine-induced cardiotoxicity: evaluation
using centrifuged solution in vivo and in isolated hearts
K. Hori*, T. Matsuura, S. Tsujikawa, T. Mori, M. Kuno and K. Nishikawa
Osaka, Japan
*E-mail: [email protected]
Editor—Lipid resuscitation is a standard rescue treatment
against local anaesthetic systemic toxicity, although the
underlying mechanism remains unclear.1–4 The partitioning effect, the trapping of lipophilic local anaesthetics into lipid
936
| Correspondence
A
NS
CAE
of
20% lipid
20% lipid
B
NS
0
20
††
**
40
60
N.S.
80
In vivo HR
(% decrease)
In vivo MAP
(% decrease)
0
CAE
20% lipid
of
20% lipid
20
40
†
60
80
N.S.
100
100
KHB
Isolated heart LVDP
(% decrease)
0
CAE
of
2% lipid
D
2% lipid
20
40
60
KHB
0
†††
***
N.S.
80
100
Isolated heart HR
(% decrease)
C
CAE
of
2% lipid
2% lipid
20
40
†
60
80
N.S.
100
Fig 1 Haemodynamic effects of bupivacaine-containing lipid solution and its CAE in vivo and in isolated hearts.  and , In in vivo models, we randomly administered
3 mg kg−1 bupivacaine in normal saline (NS), CAE of bupivacaine-containing 20% lipid emulsion (CAE of 20% lipid) or 3 mg kg−1 bupivacaine in 20% lipid emulsion
(20% lipid) at an infusion volume of 7 ml kg−1 through the left internal jugular vein for 1 min. Data are the maximal decreases during the first 15 min of
administration.  and , In isolated heart models, we sequentially perfused 30 µM bupivacaine in Krebs-Henseleit buffer (KHB), CAE of bupivacaine-containing
2% lipid solution (CAE of 2% lipid), and 30 µM bupivacaine in 2% lipid solution (2% lipid) for 15 min each, at a constant perfusion pressure of 70 mm Hg. Data are
expressed as means () (n=6 for each in vivo, and n=5 in isolated hearts). **P<0.01, *** P<0.0001, †P<0.05, ††P<0.01, †††P<0.0001 vs NS or KHB, N.S., not significant.
emulsion, is one of the most popular mechanisms,4 but its contribution separately from other lipid-specific effects has not been
determined. To distinguish the partitioning effect, we prepared
trial solutions by centrifuging bupivacaine-containing lipid solutions followed by removing the lipid layer (centrifuged aqueous
extract: CAE),5 and examined their effects on haemodynamics
in in vivo and isolated heart models. As most of the lipid emulsion
and trapped bupivacaine can be removed by the procedure
above,6 the CAE is expected to demonstrate an almost equivalent
partitioning effect to that of lipid solution, but much less lipidspecific effects other than partitioning.6 7 Therefore, our idea is
that if the effects of CAE on haemodynamics are equivalent to
those of bupivacaine-containing lipid solutions, we could gain
important evidence for the significant contribution of the partitioning effect.
After approval from the Institutional Animal Care and Use
Committee (10041, Osaka, Japan), all experiments were conducted with male Hartley guinea pigs (5–7 weeks old). For in
vivo models, the animals were anaesthetized with 2.5% sevoflurane through a tracheostomy and randomly divided into three
groups, according to the administered solution: 3 mg kg−1 bupivacaine in normal saline (NS), CAE of bupivacaine-containing 20%
lipid emulsion (CAE of 20% lipid), and bupivacaine in 20% lipid
emulsion (20% lipid). Meanwhile, the isolated hearts were sequentially perfused with 30 μM bupivacaine in Krebs-Henseleit
buffer (KHB), CAE of bupivacaine-containing 2% lipid solution
(CAE of 2% lipid), and bupivacaine in 2% lipid solution (2%
lipid). We used Intralipid 20% (Fresenius Kabi, Uppsala, Sweden)
as the lipid emulsion and diluted it one tenth with KHB in isolated hearts (2% lipid). To prepare the CAE, we centrifuged the bupivacaine-containing lipid solution at 75 000g for 20 min at 4°C.5
Statistical analyses were performed using one-way  for the
in vivo experiments and one-way repeated measures  for
the isolated heart experiments. A P-value of <0.05 was considered
statistically significant.
In in vivo models, bupivacaine-induced decrease in the mean
arterial pressure (MAP) was remarkable in the NS group (blue column; Fig. 1), and significantly smaller in the CAE (green column)
and 20% lipid ( pink column) groups. There were no significant
differences between 20% lipid and its CAE (P=0.4). Both 20%
lipid and its CAE tended to induce smaller decreases also in
heat rate (HR) compared with NS (Fig. 1B), and their decreases
were not significantly different (P=0.7). Similarly, in isolated
hearts, the bupivacaine-induced decreases in the left ventricular
developed pressure (LVDP) was remarkable in KHB (Fig. 1),
which was significantly recovered by 2% lipid solution and its
CAE with no significant differences between them (P=0.3). Both
2% lipid and its CAE tended to recover the bupivacaine-induced
decreases also in HR (Fig. 1), with no significant differences
between them (P=0.4).
In the present study, by using the CAE of a bupivacaine-containing lipid solution, we were able to show the significant contribution of the partitioning effect for bupivacaine-induced
cardiotoxicity in guinea pigs. Although the use of pre-mixed solutions does not provide the same pharmacokinetics of lipid resuscitation, the partitioning effect is the same, and we could
Correspondence
separate its contribution by using the solutions. The effects of
CAE were similar to those of bupivacaine-containing lipid solutions in both models; this suggested that the partitioning effect
is the principal mechanism in lipid resuscitation.
Acknowledgements
We thank Y. Kira and Y. Yabunaka (Central Laboratory, Osaka City
University Medical School), and Y. Okui and S. Ueno (Department
of Central Clinical Laboratory, Osaka City University Hospital) for
technical assistance. We also thank A. Asada (Osaka City University) for helpful advice.
Funding
The work was supported in part by a grant-in-aid for scientific
research from the Japan Society for the Promotion of Science
(24791619), Tokyo, Japan.
2.
3.
4.
5.
6.
Declaration of interest
None declared.
References
1. The Association of Anaesthetists of Great Britain & Ireland.
Management of severe local anaesthetic toxicity 2010.
7.
| 937
Available from http://www.aagbi.org/sites/default/files/
la_toxicity_2010_0.pdf (accessed 1 September 2015)
Neal JM, Bernards CM, Butterworth JF, et al. ASRA practice
advisory on local anesthetic systemic toxicity. Reg Anesth
Pain Med 2010; 35: 152–61
Neal JM, Mulroy MF, Weinberg GL. American Society of
Regional Anesthesia and Pain Medicine checklist for managing local anesthetic systemic toxicity: 2012 version. Reg
Anesth Pain Med 2012; 37: 16–8
Weinberg GL. Lipid emulsion infusion: resuscitation for local
anesthetic and other drug overdose. Anesthesiology 2012; 117:
180–7
Hori K, Matsuura T, Mori T, Kuno M, Sawada M, Nishikawa K.
The effect of lipid emulsion on intracellular bupivacaine as a
mechanism of lipid resuscitation. Anesth Analg 2013; 117:
1293–301
Hori K, Kuno M, Nishikawa K. Lipid emulsion increases the fast
Na+ current and reverses the bupivacaine-induced block: A
new aspect of lipid resuscitation? Anesthesiology 2014; 121:
903–4
Wagner M, Zausig YA, Ruf S, et al. Lipid Rescue Reverses the
Bupivacaine-induced Block of the Fast Na+ Current (INa) in
Cardiomyocytes of the Rat Left Ventricle. Anesthesiology 2014;
120: 724–36
doi:10.1093/bja/aev386
An alternative anaesthetic technique on nonagenerians undergoing
endovascular aortic surgery and long term outcomes
M. Lippmann*, C. Z. Kakazu, A. Karnwal, G. E. Kopchok, C. Paullin,
C. E. Donayre and R. A. White
Torrance, CA, USA
*E-mail: [email protected]
Editor—The population of the USA as a whole is aging. In the year
2000, the population older than 85 reached four million and may
exceed seven million by the year 20201. Members of this burgeoning population, particularly nonagenarians, are frequently denied access to endovascular aortic repair (EVAR) in the belief
that they are too fragile, or because of concerns about deleterious
effects of general anaesthesia. Recent systematic reviews of
treatment of abdominal aortic aneurysm (AAA) in patients >80
years of age reported pooled perioperative mortality of 7.5%
and five-year survival rate of 60% for open surgery2 and a perioperative mortality of 4.6% for EVAR.2 Even when mortality
rates are acceptable, however, the impact of treatment on quality
of life must also be considered. There has been much discussion
of possible deleterious effects of anaesthesia in the elderly, particularly with regard to negative effects on cognition (see, for example, Ghoneim3 and references therein) which may contribute
to the tendency to deny intervention to octo- and nonagenarians
with AAA. Our minimal use of anaesthesia during EVAR was designed to avoid such detrimental effects.
The subjects of this study were participants in the prospective, multicenter investigational device exemption (IDE) clinical
trial of EVAR using the AneuRx stent graft (Medtronic, Santa
Rosa, CA). Details on the methods of this approved IRB trial
have been presented.4 All subjects received the AneuRx stentgraft, an early-generation endoprosthesis with infrarenal fixation. The 13 subjects selected were ≥90 years of age between
November 1998 and January 2007. The monitoring included:
EEG, pulse oximetry, capnography, urinary catheter, oxygen
mask, blood pressure cuff on the left upper arm, skin temperature probe, and was supplemented with two large-bore i.v. and
an arterial line at the right wrist. A minimally invasive anaesthetic technique consisting of monitored anaesthesia care (MAC)
with slight sedation and peripheral nerve blocks was as follows.
After titrating i.v. fentanyl, the anaesthesiologist performed
ilioinguinal and iliohypogastric nerve blocks with 20 ml of
0.25% bupivacaine. While the nerve blocks took effect, the surgeons infiltrated 10 ml of 0.5% plain lidocaine in the groin skin
and proceeded with the operation with no waiting period. Use
of midazolam was minimized to avoid the potential respiratory
depression, confusion, and agitation sometimes observed in elderly patients as a result of synergistic effects with fentanyl. Of the
13 nonagenarian patients in our EVAR database, technical success was achieved in 100%. All patients survived the perioperative period. One patient was lost to follow-up at 22 months. All
other patients were followed until death or study termination
(mean follow-up 37 months (range, 1–73). A Kaplan-Meier