British Journal of Anaesthesia 1997; 78: 160–162
Plasma bupivacaine concentrations associated with continuous
extradural infusions in babies†
J. M. PEUTRELL, K. HOLDER AND M. GREGORY
Patients and methods
Summary
The maximum recommended dose for extradural
infusions of bupivacaine in children older than
1 month is 0.5 mg kg91 h91 but there are few specific
reports of the associated blood concentrations
during infusions in babies. Toxic symptoms can
occur in children at plasma concentrations of bupivacaine as low as 2 ␮g ml91. We attempted to
measure venous plasma concentrations of total and
free bupivacaine in babies aged 3–12 months during
extradural infusions given at a rate commonly used
in our hospital. We studied eight babies (mean age
33 weeks; mean weight 7.8 kg). After a mean initial
dose of 1.2 mg kg91 (range 1.1–1.3 mg kg91), bupivacaine was infused at a mean rate of 0.38
(0.36–0.39) mg kg91 h91 for a mean of 31 (4–44) h.
Blood was obtained at 4, 8, 16, 24, 32 and 40 h after
starting the infusion and plasma separated by
centrifugation. Total plasma bupivacaine concentration was measured using high pressure liquid chromatography (HPLC). Plasma concentrations of total
bupivacaine were mostly less than 2 ␮g ml91. One
baby had a concentration of 2.02 ␮g ml91 at 32 h and
showed clear evidence of accumulation of bupivacaine. Babies can accumulate bupivacaine and
achieve plasma concentrations above the threshold
for toxic side effects, despite infusion rates below
the currently accepted maximum. The sample size
in our study was small but we believe an extradural
infusion rate of 0.375 mg kg91 h91 is probably an
absolute maximum for babies younger than 12
months. (Br. J. Anaesth. 1997; 78: 160–162)
Key words
Anaesthesia, paediatric. Infants. Anaesthetic
extradural. Anaesthetics local, bupivacaine.
techniques,
The maximum recommended rate for extradural
infusion of bupivacaine in children older than
1 month is 0.5 mg kg91 h91.1 At the time of this
editorial there were no specific reports of blood concentrations of bupivacaine during extradural infusions in babies younger than 12 months. The aim of
our study was to measure venous plasma concentrations of both total and free bupivacaine during continuous extradural infusion of bupivacaine 0.375 mg
kg91 h91 for the duration of the infusion in babies
aged 3–12 months.
After obtaining Ethics Committee approval and
informed consent from parents, we studied babies,
aged 3–12 months, ASA I or II, undergoing major
abdominal operations. We excluded babies born
before 35 weeks’ gestation.
General anaesthesia was induced using a volatile
agent or propofol, and neuromuscular block was
produced with atracurium or vecuronium. After
intubation of the trachea the lungs were ventilated to
a normal end-tidal carbon dioxide concentration
with oxygen, nitrous oxide and a volatile agent. We
then inserted a 23-gauge lumbar extradural catheter
using a 19-gauge Tuohy needle (Portex Minipack
System) and injected bupivacaine 1.25 mg kg91
(0.25% or 0.5%). Another two doses of 0.6 mg kg91
were given if indicated by changes in heart rate or
arterial pressure, up to a maximum total dose during
surgery of 2.5 mg kg91. Continuous infusion of
0.25% bupivacaine 0.375 mg kg91 h91 (equivalent to
0.15 ml kg91 h91) was then started for postoperative
pain relief. No other analgesics were given during
anaesthesia.
A second cannula was inserted into a peripheral vein
during anaesthesia for later collection of blood samples
and flushed with heparinized saline 10 u. ml91.
After surgery the babies were monitored with an
apnoea alarm and pulse oximeter. Assessments by
nursing staff of pain and sedation using four-point
scoring systems and measurements of heart rate and
ventilatory frequency were recorded every hour. Pain
was assessed as nil, mild, moderate or severe.
Sedation was assessed as awake and alert, occasionally drowsy but easy to arouse, drowsy most of the
time but easy to arouse, or somnolent and difficult to
arouse.
Approximately 2 ml of blood were obtained from
the venous sampling cannula at 4, 8, 16, 24, 32 and
40 h after starting the continuous extradural infusion
as long as the extradural infusion was running and
the sampling cannula remained patent. Plasma was
J. M. PEUTRELL*, MRCP, FRCA, K. HOLDER, FRCA, M. GREGORY‡,
FRCA, Royal Hospital for Sick Children, St Michael’s Hill, Bristol
BS2 8EG. Accepted for publication: October 17, 1996.
*Current address for correspondence: Derriford Hospital,
Plymouth, Devon PL6 8DH.
‡Present address: Frenchay Hospital, Bristol.
†Presented to the American Society of Anesthesiologists,
Atlanta, 1995.
Plasma bupivacaine concentrations in babies
161
Table 1 Patient details, operation and loading doses, and subsequent infusion rates of extradural bupivacaine
First extradural
injection
bupivacaine
Patient
No.
Age
(wks)
Sex
Weight
(M/F) (kg)
Operation
1
2
3
18.1
19.9
45.3
M
M
F
7.6
5.7
9.1
4
5
6
7
8
Mean
40
37
21.4
48.1
34.3
M
M
M
M
M
9.3
9.1
5.6
7.0
9.3
Pyeloplasty
Closure of colostomy
Partial nephrectomy and bilateral
re-implantation of ureters
Nephro-uretectomy
Nephro-uretectomy
Nephrectomy
Bilateral re-implantation of ureters
Re-implantation of ureter
removed by centrifugation, frozen immediately and
stored at 920 ⬚C. Total bupivacaine was assayed
using a modification of a high pressure liquid
chromatography (HPLC) method described for
measurement of lignocaine and its metabolites.2 The
sensitivity of the assay was dependent on the volume
of plasma and was approximately 0.1 ␮g ml91 for
100 ␮l and 0.02 ␮g ml91 for 500 ␮l. The coefficient
of variation was 5%.
Results
We studied eight babies. Mean age was 33 weeks
(range 18–48 weeks) and mean weight 7.8 (5.6–9.3)
kg (table 1). The mean initial dose of bupivacaine
given was 1.2 (range 1.1–1.3) mg kg91. One baby
was given two additional boluses of 0.5 mg kg91
during surgery (table 1). Extradural bupivacaine
was infused at a mean rate of 0.38 (0.36–0.39) mg
kg91 h91 for a mean of 31 (4–44) h.
One catheter was removed at 4 h from a baby
undergoing laparotomy for closure of a colostomy.
The extradural infusion had seemed adequate
during surgery but after operation the baby was
intermittently distressed. This was attributed to colic
and was treated with an infusion of morphine. The
other seven babies had renal or ureteric surgery.
Their hourly pain scores were nearly all assessed as
“no pain” and no score was higher than “mild pain”.
All babies were either “awake and alert” or “drowsy
but easy to arouse” for the duration of the infusion,
except for one who was difficult to arouse at the first
assessment after returning to the ward. There was no
clinical evidence of central nervous system toxicity in
any baby.
The results for total bupivacaine plasma concentrations sampled from a peripheral vein are shown in
table 2 and figure 1. Most concentrations were less
than 2 ␮g ml91 but one baby had a concentration of
2.02 ␮g ml91 at 32 h. The same baby showed clear
evidence of accumulation of bupivacaine throughout
the extradural infusion.
We attempted to separate the free fraction of bupivacaine with a micro-partition system (Amicon) and
measure its plasma concentration using HPLC. In
most samples the volume of plasma obtained was
insufficient for the separation method or the concentration of the free drug was below the sensitivity of
Additional bolus
bupivacaine during
surgery
%
Dose
(mg kg91)
%
Dose
(mg kg91)
Rate of extradual
infusion 0.25%
bupivacaine
(mg kg h91)
0.25
0.25
1.3
1.2
—
—
—
—
0.39
0.39
0.25
0.5
0.5
0.5
0.5
0.5
1.25
1.1
1.3
1.25
1.25
1.2
1.2
0.5
—
—
—
—
—
1.1
—
—
—
—
—
0.38
0.38
0.36
0.38
0.39
0.38
0.38
Table 2 Total plasma concentrations of bupivacaine associated
with an extradural infusion sampled from a peripheral vein at
different times. All assays used 100 µl of plasma
Bupivacaine concentration (µg ml91)
Patient
No.
4h
8h
16 h
24 h
32 h
1
2
3
4
5
6
7
8
0.21
0.91
0.96
1.0
1.0
0.89
0.55
0.91
0.36
0.78
1.26
0.81
0.96
0.36
0.8
1.15
0.70
1.01
0.55
0.51
0.67
0.92
0.79
1.11
0.60
0.54
0.79
0.66
0.83
0.60
1.3
0.87
2.02
40 h
0.36
Figure 1 Venous plasma concentrations of total bupivacaine
during continuous extradural infusion, measured at 4, 8, 16, 24,
32 and 40 h.
the assay for the volumes of plasma available
(approximately 0.1 ␮g ml91 for 100 ␮l).
Discussion
Extradural analgesia for postoperative pain control
has become a more common technique in paediatric
anaesthesia since the introduction of equipment
specifically designed for use in babies and children.3–6 Plasma concentrations of local anaesthetics
during continuous extradural infusion have been
162
measured in few children,1 7 8 or babies.8 9 Babies less
than 6 months of age have an even greater potential
for local anaesthetic toxicity than older children
and adults because the free fraction of drug is
increased.10 The increased free fraction probably
results from lower concentrations of binding proteins, principally ␣1-acid glycoprotein and albumin.
The free fraction decreases inversely with age as the
plasma concentration of ␣1-acid glycoprotein
increases.
Berde reported from data collected from the
members of the Society for Pediatric Anesthesia that
seizures can occur in children at plasma concentrations of bupivacaine as low as 2 ␮g ml91.1 Our study
showed that some babies accumulate bupivacaine
during continuous extradural infusion and can reach
plasma concentrations in the range associated with
local anaesthetic toxicity in children, despite infusion
rates less than the maximum recommended by
Berde.1 This supports the findings of Wolf and
colleagues8 who showed that continuous extradural
infusion of bupivacaine in the accepted dose can
produce plasma concentrations within the toxic
range in children, and Larsson, Olsson and
Lönnqvist,9 who found that babies accumulate
bupivacaine during continuous infusions.
Wolf and colleagues measured plasma concentrations of bupivacaine associated with continuous
lumbar or thoracic extradural infusions in 20 children aged 2 months to 4 yr.8 After operation bupivacaine was infused at 0.25–0.375 mg kg91 h91 and
additional boluses were given, with a maximum dose
in any 4 h of 1.6 mg kg91. Two children, weighing 10
and 8.3 kg, had concentrations of 2.5 and 3.7 ␮g
ml91, respectively, at 24 h. No toxic side effects were
reported.
Larsson, Olsson and Lönnqvist9 measured plasma
concentrations of bupivacaine at 6 and 12 h in seven
babies aged 0–7 months given a continuous
extradural infusion.9 They injected an initial dose of
bupivacaine 1.5–1.9 mg kg91 with adrenaline and
then infused bupivacaine 0.5–0.83 mg kg91 h91
without adrenaline. These doses are greater than the
maximum recommended.1 Larsson, Olsson and
Lönnqvist9 found a marked increase in plasma concentrations between 6 and 12 h, demonstrating
accumulation of bupivacaine. The mean concentration at 6 h was 1.59 ␮g ml91 (range 1.2–2.1 ␮g ml91)
compared with 2.06 (1.53–2.98) ␮g ml91 at 12 h.
Two babies had central nervous system side effects,
British Journal of Anaesthesia
probably related to bupivacaine toxicity.
In conclusion, we have shown that babies can
accumulate bupivacaine and achieve plasma concentrations above the threshold for toxic side effects,
despite infusion rates below the currently accepted
maximum. Although we can make no comment on
the plasma concentration of unbound bupivacaine in
our patients, babies have been shown to have a
higher free fraction, at least to the age of 6 months,
and a greater potential for toxic side effects. The size
of our sample was small but we believe an extradural
infusion rate of 0.375 mg kg91 h91 is probably an
absolute maximum for babies younger than 12
months.
Acknowledgements
We thank Anne Dye (Biochemistry Technician, Sir Humphry
Davy Department of Anaesthesia, University of Bristol) for the
assays of bupivacaine.
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