Download Ropivacaine 0.75% for extradural anaesthesia in elective

British Journal of Anaesthesia 1997; 79: 3–8
CLINICAL INVESTIGATIONS
Ropivacaine 0.75% for extradural anaesthesia in elective Caesarean
section: an open clinical and pharmacokinetic study in mother and
neonate
C. P. J. MORTON, S. BLOOMFIELD, A. MAGNUSSON, H. JOZWIAK AND J. H. MCCLURE
Summary
In an open study we have investigated the efficacy
of 20 ml of 0.75% ropivacaine (7.5 mg ml91) to
provide
extradural
anaesthesia
for
elective
Caesarean section. Plasma concentrations (total
and free) were estimated in the mother and
neonate. Anaesthesia was effective and safe.
Plasma concentrations of ropivacaine in the
mother and neonate were within safe limits and
consistent with previous studies. Two mothers
received accidental i.v. injections of ropivacaine 75
mg and 150 mg, respectively, without serious
adverse effects. (Br. J. Anaesth. 1997; 79: 3–8).
Key words
Anaesthesia, obstetric. Anaesthetic techniques, extradural.
Anaesthetics
local,
ropivacaine.
Pharmacokinetics,
ropivacaine.
Ropivacaine (1-propyl-2’, 6’ pipecoloxylidide
hydrochloride monohydrate) is a new, long-acting,
amide-type local anaesthetic which has a chemical
structure similar to that of bupivacaine, the butyl
group being replaced by a propyl group. It differs
also in that it is prepared as the pure S isomer rather
than as a racemic mixture. In vivo animal studies
have suggested that central administration of both
drugs produces similar patterns of onset and extent
of sensory and motor block, but that ropivacaine has
a shorter duration of action1 and causes less motor
block.2 In humans, extradural administration of
ropivacaine produces sensory block similar to that
produced by the same volume and concentration of
bupivacaine, but motor block is slower in onset,
shorter in duration and less intense.3 In addition,
ropivacaine at similar plasma concentrations is less
cardiotoxic in both animals4 and humans.5
The advantages of extradural, rather than general,
anaesthesia for mother6 and baby7 for Caesarean
section are well documented. However, onset time is
relatively slow, block may sometimes be patchy,
asymmetrical or limited in extent, and visceral pain
may be experienced by up to 50% of patients.8
Bupivacaine 0.75% has been said to approach the
ideal for a single agent for extradural anaesthesia
for Caesarean section9 but fears of toxicity led to
withdrawal of its approval for use in obstetrics. An
agent of similar potency to, but less toxicity than,
0.75% bupivacaine could be a useful alternative
to the drugs currently available for extradural
anaesthesia for Caesarean section.
The objectives of this study were to investigate the
efficacy of 0.75% ropivacaine 20 ml to provide
extradural anaesthesia for Caesarean section, to
determine the effect of this dose of ropivacaine on
the neonate, to measure the maximum total plasma
concentration of ropivacaine in the mother, and total
and free concentrations of ropivacaine in umbilical
and maternal veins at delivery. An open design was
chosen because 0.75% ropivacaine had not been
used before in obstetric anaesthesia.
Patients and methods
Thirty-eight women (ASA I and II) carrying a
full term (艌37 weeks) singleton fetus undergoing
elective Caesarean section under extradural
anaesthesia gave informed consent to the study
which was approved by the hospital Ethics
Committee. Women with diabetes, placenta praevia,
pregnancy-induced hypertension or carrying a baby
judged small for dates were excluded, as were those
with a history of substance or alcohol abuse. Other
reasons for exclusion were height less than 152 cm or
weight more than 100 kg.
Premedication comprised ranitidine 150 mg the
night before and 2 h before operation. On arrival in
the anaesthetic room maternal heart rate and arterial
pressure were recorded, a cardiotocograph attached
and 30 ml of sodium citrate 0.3 mol litre91 given
orally. Hartmann’s solution 1 litre was administered
i.v. while the extradural catheter was inserted and
the block established.
After infiltration of the skin with lignocaine, a 16gauge Tuohy needle was inserted into the extradural
space via the first or second lumbar interspace using
a midline approach and loss of resistance to saline. A
lateral eyed extradural catheter was inserted 3–4 cm
in a cephalad direction, the catheter taped in place
C. P. J. MORTON, FRCA, J. H. MCCLURE, BSC, FRCA (Department
of Anaesthetics); S. BLOOMFIELD, MD, MRCP (Department of
Neonatal Paediatrics); Royal Infirmary of Edinburgh NHS Trust,
Lauriston Place, Edinburgh EH3 9YW. A. MAGNUSSON, MSC,
H. JOZWIAK, BA, Astra Pain Control AB, Södertälje, Sweden.
Accepted for publication: March 18, 1997.
4
and the mother turned to the wedged supine
position. Provided that neither blood nor CSF were
obtained on aspiration, 0.75% ropivacaine 3 ml were
injected as a test dose. Five minutes after the end of
the test dose, in the absence of signs of intravascular
or intrathecal injection, 0.75% ropivacaine 17 ml
were injected incrementally over 2 min.
Loss of sensation to pinprick (27-gauge shortbevel needle) was assessed at 5-min intervals for 30
min, and at 45 min and 60 min. At 60 min only the
upper sensory level was assessed because surgery had
already started. Motor block was assessed, at the
same times, according to a modified Bromage scale
(0:no motor block, 1:inability to raise extended
leg (just able to move knee), 2:inability to flex knee
(able to move foot only), 3:inability to flex ankle
joint (unable to move foot or knee)). Surgery was not
started unless there was bilateral loss of sensation to
pinprick from T6 to S3; if this had not been achieved
at 45 min, 5-ml increments of 2% lignocaine with
adrenaline 1 in 200 000 were given and the patient
withdrawn from further efficacy assessments. After
operation sensory levels and motor block were
assessed at 30-min intervals until return of normal
sensation and motor power.
Pain on skin incision, quality of analgesia, as
judged by the patient and anaesthetist, and quality of
neuromuscular block, as judged by the obstetrician,
were recorded. Times from skin incision to uterine
incision, and uterine incision to delivery, and
whether or not the uterus was exteriorized were
noted.
Maternal heart rate and arterial pressure were
measured at 3-min intervals from the end of the test
dose until the end of surgery. Fetal heart rate was
measured continuously until the start of surgery.
After surgery maternal heart rate, arterial pressure,
upper and lower sensory levels and motor power
were measured at 30-min intervals until the block
had regressed.
Evaluation of the newborn was performed by
Apgar score at 1 and 5 min after birth and by
neurological and adaptive capacity score (NACS)10
at 2 h and 24 h after delivery.
Adverse events occurring from the start of anaesthesia to discharge from hospital, either observed by
attending staff or reported by the patient in response
to standard questions, were recorded. Apart from
treatment of pain during extradural block, which was
specified in the design, decisions on management of
adverse events were made by the appropriate clinical
staff. A telephone call enquiring after the mother and
baby was made 2–3 weeks after discharge.
Maternal blood samples were obtained from a
peripheral vein immediately before administration of
the test dose, at the end of extradural injection, at
10-min intervals for 60 min and at delivery. A
sample of umbilical venous blood was obtained after
the cord was clamped. Samples of maternal and
umbilical venous blood were obtained at delivery
and pH was measured immediately on the labour
ward (Instrumentation Laboratories); all other
blood samples were centrifuged at 3000 rpm for 10
min, the plasma withdrawn and then frozen.
Samples were analysed at the end of the study by the
British Journal of Anaesthesia
Department of Bioanalysis, Astra Pain Control AB,
Södertälje, Sweden. Total concentrations of ropivacaine were measured using gas chromatography
with a nitrogen sensitive detector11 and free concentrations were measured by coupled column liquid
chromatography after ultrafiltration of the plasma
samples.12 For total concentrations the limit of
quantification was set at 0.008 mg litre91 and
interassay precision was 2.5–5.7% in the concentration range 0.027–1.141 mg litre91. For free concentrations the limit of quantification was set at 0.003
mg litre91 and interassay precision was 2.1–8.4% at
a concentration of 0.026 mg litre91. Recovery was
close to 100% for both assays. Alpha1-acid
glycoprotein (AAG) concentrations were measured
by a radioimmunodiffusion procedure.13
The following measurements were made: (1)
maternal samples: total ropivacaine concentration
immediately before the test dose, at the end of
extradural injection, at 10-min intervals for 60 min
and at delivery; free ropivacaine concentration
immediately before the test dose, at 20 min and at
delivery; AAG concentration immediately before the
test dose, and at delivery; and (2) umbilical vein
samples: total and free ropivacaine concentration
and AAG concentration.
Results
Seven patients were excluded from efficacy analysis
because of technical failure or study violation
(including two patients who received accidental i.v.
injections of ropivacaine). In addition, one patient
with poor venous access declined to have an i.v.
cannula sited for blood sampling and samples for
one patient were not frozen. Therefore, results from
31 patients were valid for analysis of efficacy and 29
for pharmacokinetic analysis. All patients who
received ropivacaine were followed-up with respect
to safety. The characteristics of the 31 patients
included in the study are shown in table 1.
Table 1 Patient characteristics (31 patients) (mean (SD) [range])
Age (yr)
Height (cm)
Weight (kg)
29.8 [23–44]
162 (6.0) [152–173]
72.5 (8.9) [54–91]
SENSORY BLOCK
Twenty-six of the 31 patients (84%) had a sensory
block to pinprick from T6 to S3 (which was defined
as adequate for surgery) at 45 min. Four patients
required increments of 2% lignocaine with
adrenaline 1 in 200 000 to achieve adequate block;
one of these had surgery delayed because the
obstetric staff were required urgently elsewhere and
eventually underwent Caesarean section under
subarachnoid block. These four patients, together
with one patient who did not develop a block below
L4, were not included in the analysis of duration of
motor and sensory block. Times to onset and
duration of sensory block at various dermatomes are
shown in table 2.
Ropivacaine 0.75% for extradural anaesthesia in Caesarean section
5
Table 2 Times to onset (min) and duration (h) of sensory and motor block (31 patients)
Onset
Sensory block
S3
S1
L5
L3
L1
T12
T10
T8
T6
Motor block
Grade I
Grade II
Grade III
Duration
Median
Quartiles
Range
Median
Quartiles
Range
23
20
15
10
5
8
10
13
15
15, 28
13, 28
13, 23
8, 15
5, 10
5, 10
8, 15
10, 15
13, 20
13–40
5–45
5–45
5–25
5–13
5–13
5–38
5–35
5–38
4.1
4.4
4.5
4.3
4.3
4.4
4.4
3.7
3.4
3.1, 5.9
3.5, 6.0
3.3, 5.5
3.4, 5.4
4.0, 5.3
4.1, 5.3
3.9, 4.7
3.3, 4.6
2.6, 3.9
2.0–7.7
1.8–7.6
2.1–7.6
2.4–7.1
1.9–7.1
1.9–6.6
2.8–6.5
1.8–6.0
1.3–5.8
18
26
25
13, 25
20, 30
25, 38
6–45
11–45
20–45
2.2
1.7
1.6
1.8, 3.1
1.5, 3.4
1.4, 2.5
1.3–5.1
1.3–4.2
1.1–3.7
MOTOR BLOCK
Of the 31 patients who were eligible for efficacy
assessment, grade I motor block developed in 30
(97%) patients, grade II in 16 (52%) and grade III in
11 (35%), at 45 min. Times to onset and duration
are shown in table 2. Sensory block outlasted motor
block by a median time of 2 h 30 min (range 1 h
15 min to 5 h 30 min).
SURGERY
Duration of the different stages of anaesthesia and
surgery are shown in table 3. Although many patients
had a block adequate for surgery within 25 min (table
2) the study design did not permit surgery to start
until 45 min after the start of extradural injection. In
addition, further delay sometimes occurred because
the operating theatre was in use.
No patient reported pain on skin incision. The
quality of anaesthesia was judged as excellent or
good by the patient and satisfactory by the
anaesthetist in 25 of the 26 patients (96%) who were
eligible for efficacy assessment, although 10 patients
(39%) reported vague symptoms suggestive of
incomplete visceral block. In one case quality of
anaesthesia was judged to be poor by the patient and
unsatisfactory by the anaesthetist. This patient, who
had an adequate somatic block, reported severe
visceral pain and required i.v. morphine when
her uterus was exteriorized for suturing. Quality of
abdominal wall muscle relaxation was judged
adequate by the obstetrician in all 26 patients.
the first 30 min; maternal heart rate was stable.
Treatment of hypotension was left to the discretion
of the anaesthetist; 25 of 31 patients were treated
with ephedrine. Fetal heart rate was stable in all but
three babies. In two of these fetal bradycardia was
associated with maternal hypotension and both
reverted to a satisfactory rate when the mothers were
turned on their left side and hypotension was
corrected. In the third, an unexplained fetal
tachycardia resolved spontaneously after 3 min
without specific action being taken.
NEONATAL ASSESSMENTS
Umbilical vein pH was normal (7.25–7.5) in all but
one baby. In this case umbilical vein pH was 7.1 and
concurrent maternal vein pH was 7.29; repeat
measurement of maternal vein blood revealed a pH
of 7.45. The baby was vigorous at birth with Apgar
scores of 7 and 10, therefore the low values were
attributed to machine measurement error. The pH
of maternal vein blood was normal (7.35–7.45) in all
but three other mothers in whom the abnormality
was slight (pH 7.32–7.34).
Thirty neonates had an Apgar score of 7 or more
at 1 min and all had a score of 9 or 10 at 5 min.
NACS at 2 and 24 h are shown in table 4.
ACCIDENTAL I.V. INJECTION OF ROPIVACAINE
There was a mean decrease in maternal systolic and
diastolic arterial pressures of 15% from baseline in
Two patients received accidental i.v. injections of
ropivacaine. In both cases the test dose of 22.5 mg (3
ml) of ropivacaine had been uneventful. The first
patient received another 7 ml of 0.75% ropivacaine
before developing unequivocal symptoms of i.v.
local anaesthetic. The injection was stopped, the
extradural catheter resited and another 3;17 ml of
0.75% ropivacaine injected. Blood samples were
Table 3 Times (min) of surgical events relative to the end of the
main dose (31 patients)
Table 4 Neurological and adaptive capacity scores (NACS)
(No. of neonates)
CARDIOVASCULAR EFFECTS
End of injection–skin incision
Skin incision–uterine incision
Skin incision–delivery
Duration of surgery
Median
Quartiles
Range
56
7.5
10
40.5
52, 61
6, 11
7, 12
32, 49.5
43–114
2–22
3–23
11–60
NACS
Time
n
30
31
32
33
34
35
36 37
38
39
2h
24 h
31
31
2
0
3
0
3
2
6
0
7
2
5
5
2
8
2
5
0
2
1
7
6
British Journal of Anaesthesia
Table 5 Maximum total concentration of ropivacaine (Cpmax),
time to Cpmax (tCpmax, total (C) and free (Cu) concentrations of
ropivacaine, and alpha1 acid glycoprotein (AAG) concentrations
in maternal and umbilical (UV) veins at specified times (n:9)
Figure 1 Total plasma concentration of ropivacaine after
administration of ropivacaine 150 mg i.v. (!) and extradural
ropivacaine 150 mg administered 28 min after ropivacaine 75
mg i.v. (●). For comparison, the data from the patients
(n:28) who received extradural ropivacaine 150 mg are shown
by the box and whisker plot. Median values are connected;
box is first and third quartiles, whiskers are maximum and
minimum values.
obtained after the end of the second 17-ml
extradural injection and at 10-min intervals thereafter. The second patient received approximately
the same dose of ropivacaine before developing
symptoms mildly suggestive of i.v. injection. The
symptoms resolved quickly when the injection was
stopped, and did not recur until the entire 20 ml of
0.75% ropivacaine had been injected. Blood samples
were obtained as soon as the extradural injection had
finished and at 10-min intervals thereafter. Plasma
concentrations in these two patients, compared with
plasma concentrations in patients who received
uneventful extradural anaesthesia are shown in
figure 1.
MISCELLANEOUS EVENTS
One baby was considered to have transient
tachypnoea of the newborn. One baby had a small
midline gum defect and one required surgery for
pyloric stenosis some weeks after discharge. One
baby was reluctant to breast feed for 4 days but fed
satisfactorily when bottle feeding was started. One
baby was reported to vomit after feeds throughout the study. When followed-up 6 weeks after
discharge, he was still vomiting occasionally but
gaining weight.
In the period between leaving the recovery room
and discharge from hospital, one mother reported
backache and two reported leg pain. No mother
complained of residual effects of extradural anaesthesia or the technique at follow-up by telephone
2–3 weeks after delivery.
PHARMACOKINETICS
In addition to the nine patients excluded from
pharmacokinetic analysis, five individual blood
samples from four other patients were excluded
because of handling errors. Valid results were available from 29 patients (table 5). Mean maximum
maternal ropivacaine concentration (CPmax) was
1.47 (SD 0.28) mg litre91, occurring at a mean time
Cpmax (mg litre91)
tCPmax (min)
Before anaesthesia
AAG (␮mol litre91)
At 20 min
C (mg litre91)
Cu (mg litre91)
fu
At delivery
C (mg litre91)
Cu (mg litre91)
fu
C (UV) (mg litre91)
Cu (UV) (mg litre91)
fu (UV)
C (UV)/C
Cu (UV)/Cu
AAG (␮mol litre91)
AAG (UV) (␮mol litre91)
Mean
SD
Range
1.47
40
0.28
13
0.94–2.39
17–63
13
4
6–28
1.36
0.10
0.08
0.28
0.03
0.02
0.86–2.28
0.05–0.16
0.04–0.13
1.25
0.09
0.07
0.37
0.06
0.18
0.31
0.74
12
5
0.32
0.04
0.02
0.18
0.02
0.06
0.17
0.16
3
2
0.78–2.39
0.05–0.23
0.03–0.11
0.20–1.12
0.04–0.09
0.06–0.29
0.12–0.84
0.32–1.06
7–22
3–14
(tCPmax) of 40 (13) min after extradural injection.
At the time of delivery, mean umbilical vein concentrations were: total 0.37 (SD 0.18) mg litre91; free
0.06 (0.015) mg litre91. Mean umbilical vein/
maternal vein (UV/MV) ratios for total and free
concentrations were 31 (17) % and 74 (16) %,
respectively. Mean free fraction (fu) in the neonates
(0.18 (0.06)) was greater than in mothers (0.07
(0.02)).
Discussion
The open design of this study prevents a true
comparison of ropivacaine with other agents for
extradural anaesthesia in Caesarean section. The
majority (84%) of our patients had a block adequate
for surgery after extradural administration of 20 ml
of 0.75% ropivacaine. Twenty-five of these patients
(96%) assessed their anaesthesia as good or
excellent. All patients had neuromuscular block that
was adequate for surgery. Noble and others,14 in a
study from the same centre, assessing adjuncts to
extradural bupivacaine for Caesarean section,
reported that 37 of 42 (88%) patients had a block
adequate for surgery after 20 ml of 0.45% bupivacaine (with adrenaline 5 ␮g ml91, fentanyl 100 ␮g,
or both) and 83% rated analgesia as good or
excellent. However, 49% of their patients required
supplementation during surgery, compared with one
of 26 in our study.
Norton, Davis and Spicer15 compared 16–20 ml
of 0.5% bupivacaine with 2% lignocaine with
adrenaline; 25% of patients required supplementary
local anaesthetic to achieve bilateral block to T6.
The procedure was pain free in only 53% of patients
and 12% reported discomfort that was distressing. In
a large retrospective clinical review, Crawford,
Davies and Lewis16 reported that approximately
12% of patients undergoing Caesarean section under
extradural anaesthesia required some form of
supplementation to their original block.
Ropivacaine 0.75% for extradural anaesthesia in Caesarean section
It was notable that we found marked separation
between the offset of motor and sensory block.
Theoretically this should provide analgesia for some
hours after return of motor function but in some
patients sensation returned in the area of the surgical
incision at a relatively early stage. Comparison of
motor block with that reported in other studies is
difficult because of the potential for observer
variation.
The cardiovascular effects were those expected of
extensive extradural block in mothers at full term.
Umbilical vein pH, used as a measure of adequate
placental perfusion, was normal in all but one case,
in whom maternal venous pH was also decreased.
These results were not consistent with the clinical
condition of either the mother or baby and as repeat
measurement of maternal venous pH was normal,
the results were considered to be spurious. Only two
babies had an unsatisfactory Apgar score at 1 min;
both improved rapidly after oxygen therapy. All
babies had satisfactory Apgar scores at 5 min.
The neurological and adaptive capacity scoring
(NACS) system10 was devised as a scoring test to
differentiate between the more generalized neurological depression associated with drugs and anaesthesia, and that associated with asphyxia or birth
trauma in term infants (艌37 weeks). A score of 35
or greater indicates a neurologically vigorous
neonate. In our study, 20 of 30 babies at 2 h and four
of 31 at 24 h had a score of less than 35. However,
there was no control group for comparison.
Ropivacaine 0.5% has been compared with 0.5%
bupivacaine for extradural anaesthesia for elective
Caesarean section.17 There were no differences
between the two drugs in terms of cardiovascular
effects or profile of sensory block. Time of onset and
intensity of motor block were the same but duration
of motor block was less with ropivacaine. There was
no difference in neonatal outcome as assessed by
Apgar score, umbilical cord blood-gas tensions or
NACS at 2 and 24 h.
One baby in our study was admitted to the special
care baby unit suffering from transient tachypnoea of
the newborn. This baby’s mother had received a
higher dose of ropivacaine than intended (225 mg, of
which 75 mg was given i.v.). Transient tachypnoea of
the newborn is attributed to delay in resorption of fetal
lung fluid after delivery and is characterized by
tachypnoea and increased oxygen requirements. The
incidence after delivery by elective Caesarean section
is approximately 9%. The chest wall is not subject to
the forces experienced in vaginal delivery and thoracic
gas volume is less. Most infants recover in 2–3 days, as
was the case in this neonate and there were no longterm sequelae. Neither transient tachypnoea of the
newborn nor the other miscellaneous events were
thought to be related to ropivacaine.
With the exception of the two women who
received accidental i.v. injections there were no
maternal symptoms attributable to central nervous
system (CNS) local anaesthetic toxicity. Scott and
colleagues5 reported early mild symptoms of CNS
toxicity at venous plasma concentrations of ropivacaine of 1–2 mg litre91. However, the subjects in
that study received i.v. infusions of ropivacaine
7
10 mg min91 and symptoms occurred within 15 min
of the start of infusion. In an earlier study the same
author18 reported that toxicity occurred at lower
peak plasma concentrations during rapid, compared
with slow, infusion of local anaesthetic. The rate of
increase and absolute value of plasma concentration
was considered to influence the development of
toxicity.
The test dose of 3 ml of 0.75% ropivacaine in our
study failed to predict intravascular catheter placement on the two occasions that accidental i.v. injection occurred. On these occasions symptoms of i.v.
local anaesthetic did not occur until another 7 ml of
0.75% ropivacaine (52.5 mg) had been injected. In
one patient the symptoms were so equivocal that the
injection was restarted when her symptoms resolved
and it was not until the injection was completed that
symptoms returned. This patient, who received a
total of 150 mg of ropivacaine i.v. had no obvious
effects other than failure to develop a block.
The time to maximum plasma concentration and
its variability in this study were almost identical to
those in a previous study19 of the same dose of
extradural ropivacaine in non pregnant patients but
the CPmax value in our study was greater and more
widely distributed. This is consistent with a study in
sheep20 which demonstrated slower clearance of
ropivacaine during pregnancy.
Local anaesthetics are small molecules which,
when unionized, are lipid soluble. The unbound,
free portion crosses the placenta readily, and at
equilibrium the free concentration is the same in the
mother and neonate.21 22 In the fetal circulation
equilibrium occurs between the bound and unbound
local anaesthetic. Plasma concentration of AAG, to
which ropivacaine is bound extensively, is less in the
neonate than in the mother, therefore total plasma
concentration of ropivacaine is less in the neonate
than in the mother, but the free fraction is greater.
In our study mean CPmax occurred before delivery
and therefore maternal plasma ropivacaine concentration was declining at the time of delivery. At this
time Cu (UV) was less than Cu (maternal vein),
implying that equilibrium between maternal and
fetal circulations had not been achieved.
In summary, 20 ml of 0.75% ropivacaine provided
safe and effective extradural anaesthesia for
Caesarean section. The commonest side effect was
hypotension, consistent with extradural block. Two
patients tolerated accidental i.v. injection of ropivacaine (75 mg and 150 mg, respectively), reporting
only early symptoms of toxicity. There were no other
adverse events attributable to systemic local anaesthetic toxicity. Maternal and umbilical vein ropivacaine concentrations were within safe limits. The
test dose of 3 ml of 0.75% ropivacaine was unreliable
in detecting intravascular catheter placement.
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